Opioid Abuse 

Types of opioids

Opioids are defined by their ability to bind to and influence opiate receptors on cell membranes. They can be divided into 3 classes:

• Naturally occurring opioids: The classic natural opioids are opium and morphine. Opium is extracted from the plant Papaver somniferum (the opium poppy), and morphine is the primary active component of opium. Endogenous neural polypeptides such and endorphins and enkephalins are also natural opioids.
• Semi-synthetic opioids: Semisynthesis is a type of chemical synthesis that uses compounds isolated from natural sources (eg, plants) as starting materials. Semi-synthetic opioids include heroin, oxycodone, oxymorphone, and hydrocodone.
• Synthetic opioids: Synthetic opioids are made using total synthesis, in which large molecules are synthesized from a stepwise combination of small and cheap (petrochemical) building blocks. Synthetic opioids include buprenorphine, methadone, fentanyl, alfentanil, levorphanol, meperidine, codeine, and propoxyphene (withdrawn from US market).

The terms opiate and narcotic are generally used interchangeably with the term opioid.

History

Opioids are the most powerful known pain relievers. Their use and abuse date back to antiquity. The pain relieving and euphoric effects of opioids were known to Sumerians (4000 BC) and Egyptians (2000 BC). International awareness of opioid abuse was stimulated early in the 20th century when President Theodore Roosevelt convened the Shanghai Opium Commission in 1909 to aid the Chinese empire in stamping out opioid addiction, especially opium smoking.

In 1913, President Woodrow Wilson's administration drafted legislation to limit the use of narcotics, requiring prescription in good faith; this became effective in 1915. Legitimate providers of narcotics and cocaine preparations were required to register with the Bureau of Internal Revenue and were mandated to keep records of transactions.

In 1917, the Harrison Narcotics Tax Act was interpreted by the courts in such a way that opioids could not be prescribed for the treatment of opioid addiction.

In the 1960s, Dole and Nyswander demonstrated that methadone was an effective treatment for opioid addiction.

In 1974, the Narcotic Addict Treatment Act allowed regulated methadone treatment for opioid addiction, but made off-label use of opioids illegal.

In 2000, the Drug Addiction Treatment Act (DATA) allowed qualified physicians to use Schedule III, IV, or V drugs for the treatment of opioid dependence. Buprenorphine is currently the only drug approved under DATA.

Opioids act by binding to opioid receptors on neurons distributed throughout the nervous system and immune system. Four major types of opioid receptors have been identified: mu, kappa, delta, and the more recently identified OFQ/N.

These receptors are the binding sites for several families of endogenous peptides, including enkephalins, dynorphins, and endorphins. These endogenous peptides regulate and modulate several important functions, including the following:

• Pain
• Stress
• Temperature
• Respiration
• Endocrine activity
• Gastrointestinal activity
• Mood
• Motivation

Understanding the role of endogenous peptides allows us to understand why medications and drugs that bind to opioid receptors have such profound effects on so many organ systems and bodily functions.

The mu opioid receptor subtype

More than 20 clinically available medications bind opioid receptors. Most of these are prototypical mu receptor full agonists (capable of producing a maximal response at mu receptor subtypes in opioid-sensitive systems), and are associated with the following constellation of effects:

• Pain relief
• Mood alteration (often producing euphoria and decreased anxiety)
• Respiratory depression (can cause death in overdose)
• Decreased gastrointestinal motility (can cause constipation)
• Cough suppression
• Suppression of corticotropin-releasing factor and adrenocorticotropin hormone
• Pinpoint pupils (miosis)
• Nausea, vomiting, pruritis (less common)

Almost all abused opioids are prototypical mu agonists. The euphoria associated with mu receptor activation is often termed a high. Moreover, when opioids are injected or inhaled, levels in the brain rise rapidly, causing a rush or thrill. The rush is a brief, intense, usually pleasurable sensation, which is followed by a longer-lasting high. When opioids are used chronically, tolerance and physical dependence occur. Over time, addicts often try to avoid unpleasant withdrawal symptoms rather than seeking the pleasurable sensations associated with initial use of opioids.

Structural brain changes

Short-term opioid use has been associated with gray matter changes in patients with chronic pain. In a small, placebo-controlled study, long-term gray matter changes correlated with the dose of morphine after only one month of use, with some changes persisting when remeasured an average of 4.7 months later.^[1]

Potential for abuse

Mu receptor agonists with rapid onset of action and short half-lives have the greatest potential for destructive addictive behaviors, as addicted individuals get immediate reward followed by noticeable withdrawal symptoms. For example, heroin typically produces the following destructive behavioral pattern:

1. Intravenous (IV) injection causes a rapid high followed, within hours, by unpleasant withdrawal symptoms.
2. These unpleasant symptoms cause the addicted individual to engage in extremely destructive and often illegal behaviors to obtain more heroin.
3. This cycle repeats itself endlessly until the addict can no longer access heroin.

Mu receptor agonists with delayed onset of action and longer half-lives, such as methadone, cause dependence without necessarily causing the same destructive cycle to occur. Methadone can be used once daily, and can be obtained legally. Once tolerance develops, methadone has little impact on mood, judgment, and psychomotor skills. Therefore, methadone can be used to replace drugs associated with more destructive lifestyles (maintenance therapy).

See the image below.

Maintenance therapy

Buprenorphine is a partial agonist at the mu receptor (it can only partially activate the receptor). Therefore the intensity of mood alteration induced by buprenorphine plateaus, and users do not generally feel the rush or intense high they feel when using other opioids. This has been termed a ceiling effect. Fortunately, buprenorphine’s partial agonism is sufficient to prevent cravings and withdrawal symptoms. Therefore, like methadone, buprenorphine can be used to replace other more destructive opioids via maintenance therapy.

Buprenorphine also binds extremely tightly to the mu receptor. This tight binding prevents other opioids from accessing the mu receptor, in turn preventing a user from getting high on other opioids. Moreover, buprenorphine’s binding is so strong that it displaces other opioids from mu receptors. Therefore, if buprenorphine is taken while a patient has significant serum levels of another opioid, the patient will rapidly experience withdrawal symptoms as the other opioid is displaced from receptors.

Mechanisms of tolerance and withdrawal

Mechanisms of tolerance and withdrawal include but are not limited to the following:

• In response to long-term exposure to relatively high doses of exogenous opioids, cells internalize their mu and delta opioid receptors. Therefore, increased opioid levels and/or increased opioid potency are necessary to generate the same effect on fewer receptors (tolerance). Similarly, once the exogenous opioids are removed from the system, the remaining endogenous opioids are unable to sufficiently activate the small number of remaining receptors (withdrawal).
• Intracellular second-messenger systems mediating the activity of opioid receptors are down-regulated in the presence of high levels of potent exogenous opioids. Therefore, even the few remaining opioid receptors cannot generate the response they were capable of prior to the administration of exogenous opioids. Down-regulated second messengers include G-proteins and adenylyl cyclase/cAMP.
• Acute tolerance can be mediated by changes in the phosphorylation patterns of mu and delta opiod receptors.

Mechanism of long-term potential for relapse

One of the most insidious features of opioid addiction is the tendency to relapse on the drug even weeks, months, or years after addicts stop using and withdrawal symptoms disappear. The mechanism for this type of relapse is being studied intensely. Animal studies suggest 3 distinct conditions that reliably induce relapse:

1. Stress
2. Exposure to conditioned cues related to past drug use
3. A dose of the previously administered drug or a drug with similar properties

There is evidence that long-term administration of opioids can permanently alter the density of dendritic spines in certain neurons, and these permanent changes may contribute to long-lasting vulnerability to relapse.

Frequency

United States

Opioid use and abuse has increased markedly in the United States starting in the 1990s and continuing through at least 2006. Increased opioid abuse coincides with the availability of high-purity heroin, which allows users to begin use by snorting or smoking, rather than by IV. Moreover, increased opioid abuse coincides with a controversial US campaign against undertreatment of pain that has caused an enormous increase in opioid prescriptions. Abuse of prescription opioids has grown particularly explosively during this time. A few statistics dramatically illustrate this problem:

• Americans constitute 4.6% of the world’s population, but consume approximately 80% of the world’s opioid supply.^[2]
• Americans consume 99% of the world’s supply of hydrocodone (the opioid component of Vicodin).
• Americans consume roughly two-thirds of the world’s illegal drugs.

The 2006 National Survey on Drug Use and Health (NSDUH), sponsored by the Substance Abuse and Mental health Services Administration (SAMHSA), provides data that graphically illustrate the increase in prescription opioid abuse in the last decade.^[3]

Between 1999 and 2006, the number of persons aged 12 and older illicitly using prescription pain relievers doubled from 2.6 to 5.2 million.

In 2006, 5.2 million surveyed persons had used prescription pain relievers illicitly in the past month, 17 times the number of people who had used heroin.

In 2006, 2.2 million persons aged 12 or older used prescription pain relievers illicitly for the first time. This is more than any other illicit drug, surpassing marijuana (2.1 million new users), and dwarfing heroin (91,000 new users). While past year initiates for prescription pain relievers increased 63% from 1997-2006, past year initiates for heroin decreased by 20% during that same period.

Prescription opioids have been suggested to be an important gateway drug, and the fact that they are prescribed by doctors lulls users into believing they are safe.

The great majority of illicitly used prescription opioids are obtained from 1 physician, not from drug dealers.

In 2006, among persons aged 12 and older who have used prescription pain relievers nonmedically in the past 12 months, the following sources were reported:

• 55.7% reported they obtained drugs free of charge from a relative or friend.
• 14.8% reported they bought or stole drugs from a relative or friend.
• 19.1% reported they obtained drugs from 1 doctor.
• Only 1.6% reported getting drugs from more than 1 doctor.
• Only 3.9% reported buying drugs from a dealer or stranger.
• Only 0.1% reported purchasing drugs on the internet.
• In cases where nonmedical users of prescription pain relievers obtained their drugs from a friend or relative for free, 80.7% of individuals reported that their friend or relative had obtained the drug from just one doctor.

Strikingly, these data suggest that drug dealers are a relatively small source of illicitly used prescription opioids. Diversion through family and friends is now the greatest source of illicit opioids, and the majority of these opioids are obtained from 1 physician, not from "doctor shopping."

Mortality/Morbidity

The progression from illicitly using opioids to opioid dependence has dire consequences, including a yearly mortality rate of approximately 2%. Moreover, sustained remission from opioid dependence is difficult to achieve.

Since 1990, data from numerous US jurisdictions have reported dramatic increases in mortality related to drug poisonings. This increase has been due primarily to unintentional drug poisonings attributed either to opioid pain relievers or unspecified drugs.

• From 1979-1990, unintentional drug poisonings increased on average 5.3% per year.
• From 1990-2002, unintentional drug poisonings increased on average 18.1% per year. This corresponded with increased prescription of opioids for pain management
• From 1999-2002, opioid analgesic poisonings on death certificates increased 91%. During the same period, fatal heroin and cocaine poisonings increased 12.4% and 22.8%, respectively.
• In 2002, 5,528 deaths were reported from prescription opioid analgesic poisonings, more than either heroin or cocaine. The increase in mortality generally corresponded to increase in sales for each prescribed opioid.
• For patients receiving opioid prescriptions, higher opioid doses were correlated with an increased risk of opioid overdose death across diagnoses and regardless of substance abuse status.^[4]

Increases in accidental heroin overdoses are postulated to stem in part from a combination of decreasing cost and increasing purity. According to the DEA, average heroin purity increased from 7% in 1980, to 48% in 2000, to 70% in 2003. This allows first-time users to get high by snorting or smoking heroin, and eventually advance to IV use when tolerance develops, making initial heroin use more palatable to some addicts. Increased purity also makes mistakes in dosing potentially more lethal.

Additionally, many users believe that risk of overdose is minimal when snorting or smoking heroin. In reality, the risk of overdose remains substantial regardless of route of administration.

Mortality rates are substantially reduced when patients are treated with methadone or buprenorphine maintenance therapy.

Opioid use and dependence are associated with significant medical and psychiatric morbidities, as well as adverse social, familial, vocational, and legal consequences. The risk of criminal activity and legal consequences becomes greater as dependence becomes more severe. Intravenous injection of opioids is associated with increased risk of blood-borne infections such as hepatitis B and C and HIV.

Many of these morbidities are reduced by substitution therapies as confirmed in a 12-month, open-label, randomized controlled trial from various German centers that examined more than 1,000 patients who were severely opioid dependent and were treated with supervised oral methadone or intravenous heroin.^[5]

Sex

Males abuse opioids more commonly than females, with the male-to-female ratio being approximately 3:1 for heroin and 1.5:1 for prescription opioids.

In a Polish study published in 1996, the direct mortality rate of people who use IV drugs was 25.7 deaths per 1000 person-years for men and 14.3 deaths per 1000 person-years for women. Compared with the general population, the risk of death was 11 times higher among males who used drugs and 20 times higher among females who used drugs.

Age

Illicit use of opioids usually begins in late adolescence or early adulthood. Experimentation with cigarettes, alcohol, and other drugs generally precedes experimentation with opioids. The period of time from initial use to dependency is extremely variable, ranging from a few weeks to several years.

A study that examined 30-year trajectories of heroin among men and women who were in methadone maintenance treatment in California in the late 1970s found that more school problems and earlier age at onset of heroin use and first arrest were associated with more persistent heroin use.^[6]