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, those with physiologic dependence 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. [7]

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 individual 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).

In 2014, the FDA announced that extended-release and long-acting (ER/LA) opioid pain relievers should be restricted for use only in the management of severe pain that requires daily, around-the-clock treatment because alternative treatments were inadequate. Labels added include warnings, which state that long-term maternal use of ER/LA opioid pain relievers could result in potentially fatal neonatal opioid withdrawal syndrome. One of the drugs approved in 2014 was hydrocodone bitartrate, an extended-release formulation with abuse-deterrent properties, designed to be hard to crush, break, dissolve, or prepare for injection. [8] These announcements were made in an effort to combat the epidemic of addiction and fatal overdoses associated with opioid abuse. [9]

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. [10]

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. The Substance Abuse and Mental Health Services Administration (SAMHSA) recommends the induction phase of buprenorphine be preceded by 12 to 24 hours of opioid abstinence in order to avoid the acute withdrawal symptoms caused by the displacement of opioid agonists from mu receptors. [11]

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 those addicted 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:

Stress 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.