- Author: Adrian Preda, MD; Chief Editor: Eduardo Dunayevich, MD more...
Opioids are powerful pain killers that are highly addictive. Opioid dependence affects nearly 5 million people in the United States and leads to approximately 17,000 deaths annually. According to the CDC, rates of opioid overdose deaths jumped significantly, from 7.9 per 100,000 in 2013 to 9.0 per 100,000 in 2014, a 14% increase. Half of deaths due to drug overdose (22,000 per year) are related to prescription drugs, according to a report on the leading cause of deaths from injury in the United States.
Signs and symptoms
Symptoms of opioid abuse can be categorized by physical state.
Patients with opioid use disorders frequently relapse and present with intoxication. Symptoms vary according to level of intoxication. For mild to moderate intoxication, individuals may present with drowsiness, pupillary constriction, and slurred speech. For severe overdose, patients may experience respiratory depression, stupor, and coma. A severe overdose may be fatal.
Symptoms of withdrawal include the following:
Autonomic symptoms - diarrhea, rhinorrhea, diaphoresis, lacrimation, shivering, nausea, emesis, piloerection
Central nervous system arousal - sleeplessness, restlessness, tremors
Pain - abdominal cramping, bone pains, and diffuse muscle aching
Craving - for the medication
See Clinical Presentation for more detail.
The Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5) defines opioid use disorder as 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:
Taking larger amounts of opioids or taking opioids over a longer period than was intended
Experiencing a persistent desire for the opioid or engaging in unsuccessful efforts to cut down or control opioid use.
Spending a great deal of time in activities necessary to obtain, use, or recover from the effects of the opioid.
Craving, or a strong desire or urge to use opioids.
Using opioids in a fashion that results in a failure to fulfill major role obligations at work, school, or home.
Continuing to use opioids despite experiencing persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids.
Giving up or reducing important social, occupational, or recreational activities because of opioid use.
Continuing to use opioids in situations in which it is physically hazardous.
Continuing to use opioids despite knowledge of having persistent or recurrent physical or psychological problems that are likely to have been caused or exacerbated by the substance.
Tolerance, as defined by either a need for markedly increased amounts of opioids to achieve intoxications or desired effect, or a markedly diminished effect with continued use of the same amount of an opioid.
Withdrawal, as manifested by either the characteristic opioid withdrawal syndrome, or taking opioids to relieve or avoid withdrawal symptoms.
Tolerance and withdrawal criteria are not considered to be met for individuals taking opioids solely under appropriate medical supervision.
Opioid use disorder can be classified by severity as mild, moderate, or severe.
See Workup for more detail.
Current guidelines recommend comprehensive treatment with pharmacological agents such as methadone, buprenorphine, or buprenorphine combined with naloxone as well as psychosocial therapy.
The American Psychiatric Association (APA) guidelines identify the following treatment modalities as effective strategies for managing opioid dependence and withdrawal.
opioid substitution with methadone or buprenorphine, followed by a gradual taper
abrupt opioid discontinuation with the use of clonidine to suppress withdrawal symptoms
The APA guidelines recommend the following evidence-based psychosocial treatments for opioid use disorder:
behavioral therapies (e.g., community reinforcement, contingency management)
cognitive-behavioral therapies (CBTs) (e.g., relapse prevention, social skills training)
psychodynamic therapy/interpersonal therapy (IPT)
group and family therapies
See Pain Management: Concepts, Evaluation, and Therapeutic Options, a Critical Images slideshow, to help assess pain and establish efficacious treatment plans.
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 following 6 opium alkaloids occur naturally: morphine, narcotine, codeine, thebaine, papaverine and narceine. Opium is extracted from the plant Papaver somniferum (the opium poppy), and morphine is the primary active component of opium. Endogenous neural polypeptides such as 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, and propoxyphene (withdrawn from US market).
The terms opiate and narcotic are generally used interchangeably with the term opioid.
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:
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:
Mood alteration (often producing euphoria and decreased anxiety)
Respiratory depression (can cause death in overdose)
Decreased gastrointestinal motility (can cause constipation)
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.
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:
- Intravenous (IV) injection causes a rapid high followed, within hours, by unpleasant withdrawal symptoms.
- These unpleasant symptoms cause the addicted individual to engage in extremely destructive and often illegal behaviors to obtain more heroin.
- 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).
The FDA announced that extended-release and long-acting (ER/LA) opioid pain relievers will be restricted for use only in the management of severe pain that requires daily, around-the-clock treatment because alternative treatments are inadequate. The labels will also include a warning stating that long-term maternal use of ER/LA opioid pain relievers can result in potentially fatal neonatal opioid withdrawal syndrome. One of these drugs is hydrocodone bitartrate, approved in 2014. This extended-release formulation has abuse-deterrent properties as the tablet is designed to be hard to crush, break, dissolve, or prepare for injection. These announcements were made in an effort to combat the epidemic of addiction and fatal overdoses associated with opioid abuse.
In 2016, the CDC released final recommendations for prescribing opioids for chronic pain to combat the epidemic of prescription overdoses. The primary recommendation states that opioids should not be first-line treatment for chronic pain. Health care providers should first consider nonopioid pain relievers or nonpharmacological options. Other recommendations include conducting a urine test before opioid therapy, starting at the lowest dose possible and avoiding doses of 90 morphine milligram equivalents (MME) or more, prescribing immediate-release as opposed to longer-acting opioids, and limiting treatment for acute pain to usually no more than 7 days.
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:
- Exposure to conditioned cues related to past drug use
- 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.
Since the 1990s, opioid use and abuse have risen markedly in the United States. The increased abuse has coincided with the availability of high-purity heroin, which allows users to begin use by snorting or smoking rather than by IV administration. Moreover, increased opioid abuse has coincided with a controversial US campaign against undertreatment of pain that has caused an enormous increase in opioid prescriptions; the growth of prescription opioid abuse has been particularly explosive. The following statistics dramatically illustrate this problem:
Americans constitute 4.6% of the world’s population, but consume approximately 80% of the world’s opioid supply 
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
An analysis from the US Centers for Disease Control and Prevention (CDC) of 2012 prescribing data collected from US retail pharmacies showed that healthcare providers wrote 259 million prescriptions for opioid painkillers that year and that 46 individuals died each day in the United States from an overdose of prescription painkillers.[11, 12, 13] The distribution of opioid painkiller prescriptions varied widely among states; healthcare providers in the highest-prescribing state (Alabama) wrote almost three times as many prescriptions per person as those in the lowest-prescribing state (Hawaii).
The 2014 National Survey on Drug Use and Health (NSDUH), sponsored by the Substance Abuse and Mental Health Services Administration (SAMHSA), also provided data graphically illustrating the increase in prescription opioid abuse. In 2014, 10,337 persons aged 12 or older had used pain relievers illicitly in the last year; 4,325 persons aged 12 or older used pain relievers illicitly in the last month.
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. In 2016, the CDC released final recommendations for prescribing opioids for chronic pain to combat the epidemic of prescription overdoses. The primary recommendation states that opioids should not be first-line treatment for chronic pain. Health care providers should first consider nonopioid pain relievers or nonpharmacological options.
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."
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. 
During 2014, a total of 47,055 drug overdose deaths occurred in the United States, representing a 1-year increase of 6.5%, from 13.8 per 100,000 persons in 2013 to 14.7 per 100,000 persons in 2014. Rates of opioid overdose deaths jumped significantly, from 7.9 per 100,000 in 2013 to 9.0 per 100,000 in 2014, a 14% increase.
In 2014, opioids were involved in 28,647 deaths, or 61% of all drug overdose deaths; the rate of opioid overdoses has tripled since 2000.
Between 2013 and 2014, the age-adjusted rate of death involving methadone remained unchanged; however, the age-adjusted rate of death involving natural and semisynthetic opioid pain relievers, heroin, and synthetic opioids, other than methadone (e.g., fentanyl) increased 9%, 26%, and 80%, respectively.
The American Pain Society has published guidelines intended to improve the safety of methadone treatment.[16, 17]
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.
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.
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.
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