Opioids are substances act on opioid receptors.

Opioids are strong analgesics, but do not provide complete analgesia regardless of whether the pain is acute or chronic in origin. 

Opioids are effective analgesics in chronic malignant pain and modestly effective in nonmalignant pain management.

When opioids are used for prolonged periods drug tolerance, chemical dependency, diversion and addiction may occur.

Medically used for pain relief, including anesthesia.


Other medical uses include:  suppression of diarrhea, for opioid use disorder, reversing opioid overdose, and suppressing cough.


Opioids are frequently used non-medically for their euphoric effects or to prevent withdrawal.


Side effects include:  itching, sedation, nausea, respiratory depression, constipation, and euphoria. 


Opioid long-term use associated with tolerance, and physical dependence.


Opioid users are at risk for physiologic and psychological dependence but also significant health consequences.


In 2017 about 70% of the US population received it or least one opioid prescription, and an  incidence of 1% would mean adverse effects in hundreds of thousands of Americans.


Tolerance refers to the fact increased doses are required to achieve the same effect.


Physical dependence: abruptly discontinuance of the drug leads to unpleasant withdrawal symptoms.


Opioid euphoric effects likelihood of recreational use.


Such escalation in recreational use manifests in addiction. 


An overdose or concurrent use with other depressant drugs like benzodiazepines can result in death from respiratory depression.


They act by binding to opioid receptors. 


Opioid receptors are found principally in the central and peripheral nervous system and the gastrointestinal tract. 


Opioids bind to specific opioid receptors in the nervous system and other tissues. 


There are three principal classes of opioid receptors, ?, ?, ? (mu, kappa, and delta).



Up to seventeen  classes of opioid receptors have been reported, and include the ?, ?, ?, and ? (Epsilon, Iota, Lambda and Zeta) receptors. 


Opioid receptors mediate psychoactive and somatic effects of opioids. 


Opioid drugs include partial agonists, like the anti-diarrhea drug loperamide and antagonists like naloxegol for opioid-induced constipation. 


Opioids do not cross the blood-brain barrier, but can displace other opioids from binding to those receptors.


Estimated 69,000 people worldwide die of opioid overdose each year and 15 million people have an opioid addiction.


Increased rates of recreational use and addiction were attributed to over-prescription of opioid medications and inexpensive illicit heroin.


Hope your prescriptions have quadrupled in the past decade, with no improvement in the prevalence of pain or disability.


Fears about over-prescribing, side effects, and addiction from opioids are similarly blamed for under-treatment of pain.


Many patients can appropriately take opioids for years without any misuse.


In a randomized trial of long-term opioid versus non-opioid pain management, the two treatment groups had similar levels of pain reduction.


In the above study the opioid group had twice as many medication related adverse effects.


Older adults and females are the most likely group to use opioids long term.


The use of opioids for chronic pain management in older individuals may be justifiable when less potent medications have been in effective or are contraindicated.


If a significant decrement in quality-of-life and functional status can be improved with opioid  therapy ongoing treatment with opioids may be a reasonable process.


Renal insufficiency in older adults reduces renal clearance of opioids, and this may lead to drug accumulation, causing neurotoxicity or respiratory depression.


Liver insufficiency in older adults can also cause in. metabolism of opioids and their metabolites and can lead to adverse effects.


CDC: 17.4% of the US population filled at least one opioid prescription in 2017, and  opioid prescribing was highest at 26.8% in the older age group of 65 years or older.


Opioids include opiates, refers to such drugs derived from opium, including morphine itself.


Chronic pain is one of the most common reasons for opioid prescriptions.


They are not more effective than other pain medications and there is minimal evidence of long term effectiveness.


Other opioids include: semi-synthetic and synthetic drugs such as hydrocodone, oxycodone and fentanyl; 


antagonist drugs such as naloxone; 


endogenous peptides such as the endorphins.


Opiate terminology is properly limited to the natural alkaloids found in the resin of the opium poppy although some include semi-synthetic derivatives.


Narcotic is a legal  term, referring  to cocaine and opioids, their source materials, and is applied to any illegal or controlled psychoactive drug.


The weak opioid codeine can be used to treat mild pain.


Other opioids are usually reserved for the relief of moderate to severe pain.


Opioids are effective for the treatment of acute pain.


For immediate relief of moderate to severe acute pain, opioids are frequently the treatment of choice, due to their rapid onset, efficacy, and reduced risk of dependence. 


There is a clear risk of prolonged opioid use when opioid analgesics are initiated for an acute pain management following surgery or trauma.


Opioids are important in palliative care to help with the severe, chronic, disabling pain that may occur in some terminal conditions such as cancer and degenerative conditions.


More than  half of all states in the US have enacted law that restrict the prescribing or dispensing of opioid for acute pain.


The risks of opioids  is greater than benefits when used for most non-cancer chronic conditions including headaches, back pain, and fibromyalgia.


The efficacy of using opioids to lessen chronic neuropathic pain is uncertain.


Their use as a first-line treatment for headache is contraindicated because they impair alertness, increase risk of dependence, and increase the risk that episodic headaches will become chronic.


Use for management of non-malignant chronic pain has led to a new and growing problem with addiction and misuse of opioids.


The use of opioids for long-term management of chronic pain is not indicated,unless other pain relievers have been found to be ineffective.


Chronic pain is better treated with medications other than opioids.


Opioids have not been found to be efficacious in placebo controlled trials for chronic non-cancer pain beyond 12-16 weeks.


With the possible exception of cancer-related bone pain, there are no pathophysiologic differences between non-cancer and cancer pain to suggest the difference in responsiveness.


Properly managing opioid use in patients with no history of substance dependence or substance abuse can give long-term pain relief with little risk of developing addiction, abuse, or other serious side effects.


Paracetamol and nonsteroidal anti-inflammatory drugs including ibuprofen and naproxen are considered safer alternatives to opioids.


These drugs are frequently used together with opioids: paracetamol combined with oxycodone (Percocet) and ibuprofen combined with hydrocodone (Vicoprofen).


Codeine-placebo-controlled trials have found that it may be no better than a placebo for some causes including acute cough in children.


In cases of diarrhea-predominate irritable bowel syndrome, opioids may be used to suppress diarrhea. 


Opioids produces constipation when opioids are used beyond several weeks.


Naloxegol, a peripherally-selective opioid antagonist is now available to treat opioid induced constipation.


They  may help with shortness of breath particularly in advanced diseases such as cancer and COPD among others.


Adverse effects: 












Dry mouth


Cognitive effects


Opioid dependence




Loss of appetite


Delayed gastric emptying


Decreased sex drive


Impaired sexual function


Decreased testosterone levels






Increased pain sensitivity


Irregular menstruation


Increased risk of falls


Slowed breathing.




In older individuals, opioid use is associated with increased risk of adverse effects:  sedation, nausea, vomiting, constipation, urinary retention, and falls with injury.


Opioids do not cause any specific organ toxicity.


Opioids are not associated with gastrointestinal bleeding and kidney toxicity.


Opioid prescriptions for acute low back pain and osteoarthritis have long-term adverse effects.


Children born to opioid-dependent mothers, are at risk for neurodevelopment impairment.


Methadone is used long-term it can build up unpredictably in the body and lead to potentially deadly slowed breathing.


Tolerance is characterized by neuroadaptations resulting in reduced drug effects. 


While receptor upregulation may play a role in tolerance, other mechanisms occur.


Tolerance varies for some effects than for others.


Tolerance develops slowly to the effects on mood, itching, urinary retention, and respiratory depression.


Tolerance, however, occurs more quickly to the analgesia and other physical side effects. 


Tolerance does not develop to constipation or miosis


Tolerance to opioids is lowered  by a number of substances including:


calcium channel blockers.


intrathecal magnesium and zinc.


NMDA antagonists, such as dextromethorphan, ketamine, and memantine.


cholecystokinin antagonists.


With tolerance the body adjusts to a medication that is present, so higher doses of the same medication are required over time to achieve the same effect. 


Tolerance does not predict any relationship of misuse or addiction. 


The quantity and the number of episodes of dispensing opioids in the first month of use is  significantly predictive  of the total duration of dispensing in the later period.


Physical dependence refers to the development of withdrawal symptoms when the substance is discontinued, when the dose is reduced abruptly or, specifically in the case of opioids, when an antagonist such as naloxone or an agonist-antagonist, such as pentazocine is administered. 


Physical dependence does not necessarily imply that the patient is addicted.


Opioid withdrawal symptoms: dysphoria, craving for another opiate dose, irritability, sweating, nausea, rhinorrea, tremor, vomiting, and myalgia. 


Slowly reducing dosage opioids over days and weeks can reduce or eliminate the withdrawal symptoms.


The timing and severity of opioid withdrawal depends on the half life of the drug: heroin and morphine withdrawal occur more quickly than methadone withdrawal. 


Acute withdrawal is often followed by depression and insomnia that can last for months. 


Opioid withdrawal can be treated with medications, including clonidine.


Physical dependence does not predict drug misuse or true addiction.


Physical dependence is closely related to the same mechanism as tolerance. 


Opioid drug addiction is typically associated with misuse of certain drugs, developing over time and with higher drug dosages. 


Addiction includes psychological compulsion.


The addict  sufferers persists in actions leading to dangerous or unhealthy outcomes. 


Synthetic opioids like those of the pentazocine, levorphanol, fentanyl, pethidine, methadone are more associated with this side effect than natural opioids like morphine and codeine and semi-synthetics like hydromorphone, which appears to be a stronger correlation with the relative analgesic strength. 


Opioid addiction includes other than oral use, by insufflation or injection.


Slow-release opioid formulations of medications are intended to curb abuse and addiction rates while trying to still provide legitimate pain relief and ease of use to pain patients. 


The long-term use of opioids can cause hyperalgesia, with increased sensitivity to pain.


Common adverse reactions to opioids: nausea and vomiting, drowsiness, itching, dry mouth, dizziness, and constipation.


Generally, tolerance to nausea occurs within 7�10 days.


Opioid induced vomiting may be due to gastric stasis, esophageal reflux, epigastric fullness, early satiety, as well as direct influence on the chemoreceptor trigger zone of the area post streamer, and vomiting center of the brain.


Opioid-induced vomiting can be prevented by prokinetic agents such as metoclopramide.


With the use in chronic pain, there are small improvements in pain and physical functioning, but there is increased risk for vomiting.


Tolerance to drowsiness usually manifests develops over 5-7 days.


Certain of the opioids such as fentanyl, morphine and heroin are sedating.


Oxycodone, and meperidine tend to produce less sedation.


There is individual variation in sedation with the use of opioids.


With bothersome and persistent sedation CNS stimulants is generally effective, and include caffeine, modafinil, amphetamine, methylphenidate.


Itching is a common problem when opioids are used for pain relief.


Antihistamines are useful for counteracting itching when it occurs. 


Several opioid/antihistamine combination products are available.


((Opioid-induced constipation)) (OIC) develops in 90 to 95% of people taking opioids long-term.


Treatment of Opioid-induced constipation is dependent on severity.


The first line treatment of Opioid-induced constipation is non-pharmacological, and includes lifestyle modifications like increasing dietary fiber, fluid intake, and physical activity.


If non-pharmacological measures are not successfully, laxatives, including stool softeners, bulk-forming laxatives, stimulant laxatives and/or enemas, may be used.


Peripherally acting u-opioid receptor antagonists are effective and durable for patients with OIC.


Opioid formulations or regimens that include a peripherally-selective opioid antagonist, such as methylnaltrexone bromide, naloxegol, alvimopan, or naloxone may be tried for opioid induced constipation.


Naloxone by mouth appears to be the most effective.


Naldemedine has been shown to significantly improve symptoms in patients with OIC.


Tramadol, tapentadol, methadone and fentanyl may cause relatively less constipation, while 


 codeine, morphine, oxycodone or hydromorphone are associated with more constipation.


Respiratory depression is the most serious associated adverse reaction.


Respiratory depression with opioids is 


usually seen with the use of a single, intravenous dose in an opioid-naive patient. 


Tolerance to respiratory depression occurs rapidly, so that it is not a clinical problem in patients with chronic use of opioids for pain.


The only respiratory stimulant currently approved is doxapram.


After opioid administration the first 24 hours appear to be the most critical with regard to life-threatening opioid induced respiratory distress.


Patients with cardiac, respiratory disease and/or obstructive sleep apnoea are at increased risk for opioid induced respiratory distress.


Opioid-induced hyperalgesia has been observed in some people. 


Opioid induced hyperalgesia is more commonly with chronic use or high doses.


Hyperalgesia allodynia, and worsening of neuropathic pain, may be consequences of long-term treatment with opioid analgesics.


Altered pain suggested to be a result of actions of opioid drugs on targets other than the classic opioid receptors, including the nociceptin receptor, sigma receptor and Toll-like receptor.


Medical and recreational opioid use is associated with hypogonadism is related to low sex hormone levels in  both sexes. 


The effect is dose-dependent, so that as many as 90% of chronic opioid users suffer from hypogonadism. 


Opioids can also interfere with menstruation by limiting the production of luteinizing hormone.


Opioid-induced hypogonadism is probably related to the association of opioid use with osteoporosis and bone fracture, due to deficiency in estradiol. 


The depressed testosterone levels of heroin addicts returned to normal within one month of abstinence, suggesting that the effect is reversible.


Use of opioids is a risk factor for failing to return to work, for 


performing any safety-sensitive tasks, for driving and using heavy equipment, and for perform safety-sensitive operations should assign workers to less sensitive duties for so long as those workers are treated by their physician with opioids.


Long-term use of opioids associated with unemployment, and can become barriers to patients having an active life, gaining employment, and sustaining a career.


Unemployment may be a predictor of abusive use of prescription opioids.


Opioid use increased accident-proneness, risk of traffic accidents and accidental falls.


Opioid use alone reduce attention, and when used with antidepressants and/or anticonvulsants this problem is intensified, 


Opioid associated side effects: 


dose-related respiratory depression, confusion, hallucinations, delirium, urticaria, hypothermia, bradycardia/tachycardia, orthostatic hypotension, dizziness, headache, urinary retention, ureteric or biliary spasm, muscle rigidity, myoclonus with high doses, 


and flushing due to histamine release, except fentanyl and remifentanil.


Opioids decrease the proliferation of macrophage progenitor cells and lymphocytes, inhibit WBC migration and affect cell differentiation affecting the immmune system.


The combined use of opioids with antidepressants,  benzodiazepines or ethanol increases the rates of adverse events and overdose.


The combination of an opioid and another depressant may precipitate respiratory depression  and death.


Opioid effects can be reversed with an opioid antagonist such as naloxone or naltrexone.


Competitive opioid antagonists bind to the opioid receptors with higher affinity than agonists, but  do not activate the receptors. 


Displacing the agonist, attenuated  or reverses  the agonist effects. 


The  elimination half-life of naloxone can be shorter than that of the opioid itself, so repeat dosing or continuous infusion may be required.


Opioids are only partially reversed to avoid a severe excruciating pain, so 


small doses of naloxone are given until the respiratory rate has improved. 


An infusion is subsequently used to keep the reversal at that level, while maintaining pain relief. 


Opioid analgesics, are useful for treating overdose, and  alongside opioid analgesics to reduce side effects.


Opioid analgesic use requires dose titration to allow analgesia to be maintained.


Opioid receptors are all G-protein coupled receptors acting on GABAergic neurotransmission.


The response to an opioid depends upon: the receptor to which it binds, its affinity for that receptor, and whether the opioid is an agonist or an antagonist. 


The analgesic properties of the opioid agonist morphine are mediated by activation of the ?1 receptor, while its 


respiratory depression and physical dependence by the ?2 receptor; and sedation and spinal analgesia by the ? receptor.


The  various classes of opioid receptors are activated at different magnitudes according to the specific receptor binding affinities of the opioid.


Equianalgesic tables are used to find the equivalent dosage of another opioid.


Such tables describe an opioid by comparison to morphine, the reference opioid. 


In 2017 about 3.4 percent of the U.S. population were prescribed opioids for daily pain management.


Centers for Disease Control and Prevention recommends  that opioids only be used when benefits for pain and function are expected to outweigh risks, and then used at the lowest effective dosage, with avoidance of concurrent opioid and benzodiazepine use whenever possible.


Because opioids can produce strong feelings of euphoria they are frequently used recreationally, and are associated with illicit opioids such as heroin.


Prescription opioids are also misused recreationally.


Opioid misuse can also include providing medications to persons for whom it was not prescribed. 


Types of opioids:


Natural opiates: alkaloids contained in the resin of the opium poppy, primarily morphine, codeine, and thebaine.


Semi-synthetic opioids: created from either the natural opiates or morphine esters, such as hydromorphone, hydrocodone, oxycodone, oxymorphone, ethylmorphine and buprenorphine.


Fully synthetic opioids: such as fentanyl, pethidine, levorphanol, methadone, tramadol, tapentadol, and dextropropoxyphene.


Endogenous opioid peptides, produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphins. 


Tricyclic antidepressants have painkilling effect as well, but they’re thought to do so by indirectly activating the endogenous opioid system. 


Other analgesics work peripherally.


Opioid receptors are also present on peripheral sensory neurons.


A significant fraction of up to 60% of opioid analgesia can be mediated by such peripheral opioid receptors, particularly in inflammatory conditions such as arthritis, traumatic or surgical pain.


Inflammatory pain blunted by endogenous opioid peptides activating peripheral opioid receptors.


Dextromethorphan is a semi-synthetic opioid agonist and its metabolite dextrorphan have no opioid analgesic effect.


 Dextromethorphan is a  potent NMDA antagonists used in many over-the-counter cough suppressants.


Opioid-peptides that are produced in the body include:










Black and Hispanic patients are less likely to receive opioid analgesics than  white patients. 


When black and Hispanic patients do receive opioids they commonly receive a lower dose an White counterparts.



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