Opioids are substances that act on opioid receptors to produce
morphine-like effects. Medically they are primarily used for pain
relief, including anesthesia. Other medical uses include
suppression of diarrhea, replacement therapy for opioid use disorder,
reversing opioid overdose, suppressing cough, and suppressing opioid
induced constipation. Extremely potent opioids such as carfentanil
are only approved for veterinary use. Opioids are also frequently
used non-medically for their euphoric effects or to prevent
Side effects of opioids may include itchiness, sedation, nausea,
respiratory depression, constipation, and euphoria. Tolerance and
dependence will develop with continuous use, requiring increasing
doses and leading to a withdrawal syndrome upon abrupt
discontinuation. The euphoria attracts recreational use, and frequent,
escalating recreational use of opioids typically results in addiction.
An overdose or concurrent use with other depressant drugs commonly
results in death from respiratory depression.
Opioids act by binding to opioid receptors, which are found
principally in the central and peripheral nervous system and the
gastrointestinal tract. These receptors mediate both the psychoactive
and the somatic effects of opioids.
Opioid drugs include partial
agonists, like the anti-diarrhea drug loperamide and antagonists like
naloxegol for opioid-induced constipation, which do not cross the
blood-brain barrier, but can displace other opioids from binding in
Because of opioid drugs' reputation for addiction and fatal overdose,
most are controlled substances. In 2013, between 28 and 38 million
people used opioids illicitly (0.6% to 0.8% of the global population
between the ages of 15 and 65). In 2011, an estimated 4 million
people in the United States used opioids recreationally or were
dependent on them. As of 2015, increased rates of recreational use
and addiction are attributed to over-prescription of opioid
medications and inexpensive illicit heroin. Conversely,
fears about over-prescribing, exaggerated side effects and addiction
from opioids are similarly blamed for under-treatment of pain.
2 Medical uses
2.1.1 Acute pain
2.1.2 Chronic non-cancer pain
Diarrhea and constipation
2.2.3 Shortness of breath
3 Adverse effects
3.1 Reinforcement disorders
3.1.2 Physical dependence
Nausea and vomiting
3.6 Respiratory depression
3.7 Opioid-induced hyperalgesia
3.8 Other adverse effects
3.8.1 Hormone imbalance
3.8.2 Disruption of work
3.8.3 Increased accident-proneness
3.8.4 Rare side effects
4.1 With other depressant drugs
5.1 Functional selectivity
5.3 Binding profiles
8 Society and culture
8.2 Efforts to reduce abuse in the US
8.3 Global shortages
8.4 Recreational use
8.5 Rational use
Opium alkaloids and derivatives
9.2.2 Esters of morphine
9.2.3 Ethers of morphine
9.2.4 Semi-synthetic alkaloid derivatives
9.3 Synthetic opioids
9.3.3 Diphenylpropylamine derivatives
9.3.4 Benzomorphan derivatives
9.3.6 Morphinan derivatives
9.4 Allosteric modulators
9.6 Tables of opioids
9.6.1 Table of morphinan opioids
9.6.2 Table of non-morphinan opioids
10 See also
12 External links
Opioids include opiates, an older term that refers to such drugs
derived from opium, including morphine itself. Other opioids are
semi-synthetic and synthetic drugs such as hydrocodone, oxycodone and
fentanyl; antagonist drugs such as naloxone; and endogenous peptides
such as the endorphins. The terms opiate and narcotic are
sometimes encountered as synonyms for opioid.
Opiate is properly
limited to the natural alkaloids found in the resin of the opium poppy
although some include semi-synthetic derivatives. Narcotic,
derived from words meaning 'numbness' or 'sleep', as an American legal
term, refers to cocaine and opioids, and their source materials; it is
also loosely applied to any illegal or controlled psychoactive
drug. In some jurisdictions all controlled drugs are legally
classified as narcotics. The term can have pejorative connotations and
its use is generally discouraged where that is the case.
Opioids are indicated for the relief of mild to severe pain, but
are usually reserved for moderate to severe pain. The weak opioid
codeine, in low doses and combined with one or more other drugs, is
commonly available without a prescription.
Opioids are effective for the treatment of acute pain (such as pain
following surgery). 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. They have also
been found to be 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 such as rheumatoid
arthritis. In many cases opioids are a successful long-term care
strategy for those with chronic cancer pain.
Chronic non-cancer pain
Guidelines have suggested that the risk of opioids is likely greater
than their benefits when used for most non-cancer chronic conditions
including headaches, back pain, and fibromyalgia. Thus they should
be used cautiously in chronic non-cancer pain. If used the
benefits and harms should be reassessed at least every three
In treating chronic pain, opioids are an option to be tried after
other less risky pain relievers have been considered, including
paracetamol/acetaminophen or NSAIDs like ibuprofen or naproxen.
Some types of chronic pain, including the pain caused by fibromyalgia
or migraine, are preferentially treated with drugs other than
opioids. The efficacy of using opioids to lessen chronic
neuropathic pain is uncertain.
Opioids are contraindicated as a first-line treatment for headache
because they impair alertness, bring risk of dependence, and increase
the risk that episodic headaches will become chronic. Opioids can
also cause heightened sensitivity to headache pain. When other
treatments fail or are unavailable, opioids may be appropriate for
treating headache if the patient can be monitored to prevent the
development of chronic headache.
Opioids are being used more frequently in the management of
non-malignant chronic pain. This practice has now led to a
new and growing problem with addiction and misuse of opioids.
Because of various negative effects the use of opioids for long term
management of chronic pain is not indicated unless other less risky
pain relievers have been found ineffective.
Chronic pain which occurs
only periodically, such as that from nerve pain, migraines, and
fibromyalgia, frequently is better treated with medications other than
Paracetamol and nonsteroidal anti-inflammatory drugs
including ibuprofen and naproxen are considered safer
alternatives. They are frequently used combined with opioids, such
as paracetamol combined with oxycodone (Percocet) and ibuprofen
combined with hydrocodone (Vicoprofen), which boosts the pain relief
but is also intended to deter recreational use.
Codeine was once viewed as the "gold standard" in cough suppressants,
but this position is now questioned. Some recent
placebo-controlled trials have found that it may be no better than a
placebo for some causes including acute cough in children.
Thus, it is not recommended for children. Additionally, there is
no evidence that hydrocodone is useful in children. Similarly, a
2012 Dutch guideline regarding the treatment of acute cough does not
recommend its use. (The opioid analogue dextromethorphan, long
claimed to be as effective a cough suppressant as codeine, has
similarly demonstrated little benefit in several recent studies.)
Low dose morphine may help chronic cough but its use is limited by
Diarrhea and constipation
In cases of diarrhea-predominate irritable bowel syndrome, opioids may
be used to suppress diarrhea.
Loperamide is a peripherally selective
opioid available without a prescription used to suppress diarrhea.
The ability to suppress diarrhea also produces constipation when
opioids are used beyond several weeks. Naloxegol, a
peripherally-selective opioid antagonist is now available to treat
opioid induced constipation.
Shortness of breath
Opioids may help with shortness of breath particularly in advanced
diseases such as cancer and
COPD among others.
Adverse effects of opioids
Common and short term
Decreased sex drive
Impaired sexual function
Decreased testosterone levels
Increased pain sensitivity
Increased risk of falls
In older adults, opioid use is associated with increased adverse
effects such as "sedation, nausea, vomiting, constipation, urinary
retention, and falls". As a result, older adults taking opioids
are at greater risk for injury. Opioids do not cause any specific
organ toxicity, unlike many other drugs, such as aspirin and
paracetamol. They are not associated with upper gastrointestinal
bleeding and kidney toxicity.
Research suggests that when methadone is used long-term it can build
up unpredictably in the body and lead to potentially deadly slowed
breathing. Used medically, approaching toxicity goes
unrecognized because the pain medication effect ends long before the
drug's elimination half-life. According to the USCDC, methadone
was involved in 31% of opioid related deaths in the US between
1999-2010 and 40% as the sole drug involved, far higher than other
opioids. Studies of long term opioids have found that may stop
them and minor side effects were common. Addition occurred in
about 0.3%. In the United States in 2016 opioid overdose resulted
in the death of 1.7 in 10,000 people.
US yearly deaths involving prescription opioids. Non-methadone
synthetics is a category dominated by illegally acquired fentanyl, and
has been excluded.
US yearly deaths from all opioid drugs. Included in this number are
opioid analgesics, along with heroin and illicit synthetic
US yearly overdose deaths involving heroin.
US yearly illicit opioid deaths. Number of deaths from heroin and
Opioid use disorder
Tolerance is a process characterized by neuroadaptations that result
in reduced drug effects. While receptor upregulation may often play an
important role other mechanisms are also known. Tolerance is more
pronounced for some effects than for others; tolerance occurs slowly
to the effects on mood, itching, urinary retention, and respiratory
depression, but occurs more quickly to the analgesia and other
physical side effects. However, tolerance does not develop to
constipation or miosis (the constriction of the pupil of the eye to
less than or equal to two millimeters). This idea has been challenged,
however, with some authors arguing that tolerance does develop to
Tolerance to opioids is attenuated by a number of substances,
calcium channel blockers
intrathecal magnesium and zinc
NMDA antagonists, such as dextromethorphan, ketamine, and
cholecystokinin antagonists, such as proglumide
Newer agents such as the phosphodiesterase inhibitor ibudilast have
also been researched for this application.
Tolerance is a physiologic process where the body adjusts to a
medication that is frequently present, usually requiring higher doses
of the same medication over time to achieve the same effect. It is a
common occurrence in individuals taking high doses of opioids for
extended periods, but does not predict any relationship to misuse or
Physical dependence is the physiological adaptation of the body to the
presence of a substance, in this case opioid medication. It is defined
by 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 (e.g., naloxone) or an
agonist-antagonist (e.g., pentazocine) is administered. Physical
dependence is a normal and expected aspect of certain medications and
does not necessarily imply that the patient is addicted.
The withdrawal symptoms for opiates may include severe dysphoria,
craving for another opiate dose, irritability, sweating, nausea,
rhinorrea, tremor, vomiting and myalgia. Slowly reducing the intake of
opioids over days and weeks can reduce or eliminate the withdrawal
symptoms. The speed and severity of withdrawal depends on the
half-life of the opioid; heroin and morphine withdrawal occur more
quickly than methadone withdrawal. The acute withdrawal phase is often
followed by a protracted phase of depression and insomnia that can
last for months. The symptoms of opioid withdrawal can be treated with
other medications, such as clonidine. Physical dependence does not
predict drug misuse or true addiction, and is closely related to the
same mechanism as tolerance. While there is anecdotal claims of
benefit with ibogaine, data to support its use in substance dependence
Drug addiction is a complex set of behaviors typically associated with
misuse of certain drugs, developing over time and with higher drug
Addiction includes psychological compulsion, to the extent
that the sufferer persists in actions leading to dangerous or
Opioid addiction includes insufflation or
injection, rather than taking opioids orally as prescribed for medical
In European nations such as Austria, Bulgaria, and Slovakia, slow
release oral morphine formulations are used in opiate substitution
therapy (OST) for patients who do not well tolerate the side effects
of buprenorphine or methadone. In other European countries including
the UK, this is also legally used for OST although on a varying scale
Tamper-release formulations of time-controlled preparations 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. Questions remain, however, about the efficacy and safety of
these types of preparations. Further tamper resistant medications are
currently under consideration with trials for market approval by the
The amount of evidence available only permits making a weak
conclusion, but it suggests that a physician 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.
Problems with opioids include the following:
Some people find that opioids do not relieve all of their pain.
Some people find that opioids side effects cause problems which
outweigh the therapy's benefit
Some people build tolerance to opioids over time. This requires them
to increase their drug dosage to maintain the benefit, and that in
turn also increases the unwanted side effects.
Long-term opioid use can cause opioid-induced hyperalgesia, which is a
condition in which the patient has increased sensitivity to pain.
All of the opioids can cause side effects. Common adverse
reactions in patients taking opioids for pain relief include nausea
and vomiting, drowsiness, itching, dry mouth, dizziness, and
Nausea and vomiting
Tolerance to nausea occurs within 7–10 days, during which
antiemetics (e.g. low dose haloperidol once at night) are very
effective. Due to severe side effects such as tardive
dyskinesia, haloperidol is now rarely used. A related drug,
prochlorperazine is more often used, although it has similar risks.
Stronger antiemetics such as ondansetron or tropisetron are sometimes
used when nausea is severe or continuous and disturbing, despite their
greater cost. A less expensive alternative is dopamine antagonists
such as domperidone and metoclopramide.
Domperidone does not cross the
blood–brain barrier and produce adverse central antidopaminergic
effects, but blocks opioid emetic action in the chemoreceptor trigger
zone. (The drug is not available in the U.S.) Some antihistamines with
anticholinergic properties (e.g. orphenadrine or diphenhydramine) may
also be effective. The first-generation antihistamine hydroxyzine is
very commonly used, with the added advantages of not causing movement
disorders, and also possessing analgesic-sparing properties.
Δ9-tetrahydrocannabinol relieves nausea and vomiting; it also
produces analgesia that may allow lower doses of opioids with reduced
nausea and vomiting.
5-HT3 antagonists (e.g. ondansetron)
Dopamine antagonists (e.g. domperidone)
Anti-cholinergic antihistamines (e.g. diphenhydramine)
Δ9-tetrahydrocannabinol (e.g. dronabinol)
Vomiting is due to gastric stasis (large volume vomiting, brief nausea
relieved by vomiting, oesophageal reflux, epigastric fullness, early
satiation), besides direct action on the chemoreceptor trigger zone of
the area postrema, the vomiting centre of the brain. Vomiting can thus
be prevented by prokinetic agents (e.g. domperidone or
metoclopramide). If vomiting has already started, these drugs need to
be administered by a non-oral route (e.g. subcutaneous for
metoclopramide, rectally for domperidone).
Prokinetic agents (e.g. domperidone)
Anti-cholinergic agents (e.g. orphenadrine)
Tolerance to drowsiness usually develops over 5–7 days, but if
troublesome, switching to an alternative opioid often helps. Certain
opioids such as fentanyl, morphine and diamorphine (heroin) tend to be
particularly sedating, while others such as oxycodone, tilidine and
meperidine (pethidine) tend to produce comparatively less sedation,
but individual patients responses can vary markedly and some degree of
trial and error may be needed to find the most suitable drug for a
particular patient. Otherwise, treatment with CNS stimulants is
Stimulants (e.g. caffeine, modafinil, amphetamine, methylphenidate)
Itching tends not to be a severe problem when opioids are used for
pain relief, but antihistamines are useful for counteracting itching
when it occurs. Non-sedating antihistamines such as fexofenadine are
often preferred as they avoid increasing opioid induced drowsiness.
However, some sedating antihistamines such as orphenadrine can produce
a synergistic pain relieving effect permitting smaller doses of
opioids be used. Consequently, several opioid/antihistamine
combination products have been marketed, such as Meprozine
(meperidine/promethazine) and Diconal (dipipanone/cyclizine), and
these may also reduce opioid induced nausea.
Antihistamines (e.g. fexofenadine)
Opioid-induced constipation (OIC) develops in 90 to 95% of people
taking opioids long-term. Since tolerance to this problem does not
develop readily, most people on long-term opioids need to take a
laxative or enemas. While all opioids cause constipation, there
are some differences between drugs, with studies suggesting tramadol,
tapentadol, methadone and fentanyl may cause relatively less
constipation, while with codeine, morphine, oxycodone or hydromorphone
constipation may be comparatively more severe.
Opioid rotation is
commonly used to try and minimise the impact of constipation in
Treatment of OIC is successional and dependent on severity. The
first mode of treatment is non-pharmacological, and includes lifestyle
modifications like increasing dietary fiber, fluid intake (around
1.5 L (51 US fl oz) per day), and physical
activity. If non-pharmacological measures are ineffective,
laxatives, including stool softeners (e.g., docusate), bulk-forming
laxatives (e.g., fiber supplements), stimulant laxatives (e.g.,
bisacodyl, senna), and/or enemas, may be used. A common laxative
regimen for OIC is the combination of docusate and
bisacodyl. Osmotic laxatives, including lactulose,
polyethylene glycol, and milk of magnesia (magnesium hydroxide), as
well as mineral oil (a lubricant laxative), are also commonly used for
If laxatives are insufficiently effective (which is often the
case), opioid formulations or regimens that include a
peripherally-selective opioid antagonist, such as methylnaltrexone
bromide, naloxegol, alvimopan, or naloxone (as in oxycodone/naloxone),
may be tried. A 2008 Cochrane review found that the
evidence was tentative for alvimopan, naloxone, or methylnaltrexone
Respiratory depression is the most serious adverse reaction associated
with opioid use, but it usually is seen with the use of a single,
intravenous dose in an opioid-naïve patient. In patients taking
opioids regularly for pain relief, tolerance to respiratory depression
occurs rapidly, so that it is not a clinical problem. Several drugs
have been developed which can partially block respiratory depression,
although the only respiratory stimulant currently approved for this
purpose is doxapram, which has only limited efficacy in this
application. Newer drugs such as
CX-546 may be
much more effective.[non-primary source needed]
Respiratory stimulants: carotid chemoreceptor agonists (e.g.
doxapram), 5-HT4 agonists (e.g. BIMU8), δ-opioid agonists (e.g.
BW373U86) and AMPAkines (e.g. CX717) can all reduce respiratory
depression caused by opioids without affecting analgesia, but most of
these drugs are only moderately effective or have side effects which
preclude use in humans. 5-HT1A agonists such as
repinotan also counteract opioid-induced respiratory depression, but
at the same time reduce analgesia, which limits their usefulness for
Opioid antagonists (e.g. naloxone, nalmefene, diprenorphine)
Main article: Opioid-induced hyperalgesia
Opioid-induced hyperalgesia – where individuals using opioids to
relieve pain paradoxically experience more pain as a result of that
medication – has been observed in some people. This phenomenon,
although uncommon, is seen in some people receiving palliative care,
most often when dose is increased rapidly. If encountered,
rotation between several different opioid pain medications may
decrease the development of increased pain.
hyperalgesia more commonly occurs with chronic use or brief high doses
but some research suggests that it may also occur with very low
Side effects such as hyperalgesia and allodynia, sometimes accompanied
by a worsening of neuropathic pain, may be consequences of long-term
treatment with opioid analgesics, especially when increasing tolerance
has resulted in loss of efficacy and consequent progressive dose
escalation over time. This appears to largely be a result of actions
of opioid drugs at targets other than the three classic opioid
receptors, including the nociceptin receptor, sigma receptor and
Toll-like receptor 4, and can be counteracted in animal models by
antagonists at these targets such as J-113,397,
(+)-naloxone respectively. No drugs are currently approved
specifically for counteracting opioid-induced hyperalgesia in humans
and in severe cases the only solution may be to discontinue use of
opioid analgesics and replace them with non-opioid analgesic drugs.
However, since individual sensitivity to the development of this side
effect is highly dose dependent and may vary depending which opioid
analgesic is used, many patients can avoid this side effect simply
through dose reduction of the opioid drug (usually accompanied by the
addition of a supplemental non-opioid analgesic), rotating between
different opioid drugs, or by switching to a milder opioid with a
mixed mode of action that also counteracts neuropathic pain,
particularly tramadol or tapentadol.
NMDA antagonists such as ketamine
SNRIs such as milnacipran
anticonvulsants such as gabapentin or pregabalin
Other adverse effects
Clinical studies have consistently associated medical and recreational
opioid use with hypogonadism and hormone imbalance in different sexes.
The effect is dose-dependent. Most studies suggest that the majority
(perhaps as much as 90%) of chronic opioid users suffer hormone
imbalances. Opioids can also interfere with menstruation in women by
limiting the production of luteinizing hormone (LH). Opioid-induced
endocrinopathy likely causes the strong association of opioid use with
osteoporosis and bone fracture. It also may increase pain and thereby
interfere with the intended clinical effect of opioid treatment.
Opioid-induced endocrinopathy is likely caused by their agonism of
opioid receptors in the hypothalamus and the pituitary gland.[citation
needed] One study found that the depressed testosterone levels of
heroin addicts returned to normal within one month of abstinence,
suggesting that the effect is not permanent. As of
2013[update], the effect of low-dose or acute opiate use on the
endocrine system is unclear.
Disruption of work
Use of opioids may be a risk factor for failing to return to
Persons performing any safety-sensitive task should not use
opioids. Health care providers should not recommend that workers
who drive or use heavy equipment including cranes or forklifts treat
chronic or acute pain with opioids. Workplaces which manage
workers who perform safety-sensitive operations should assign workers
to less sensitive duties for so long as those workers are treated by
their physician with opioids.
People who take opioids long term have increased likelihood of being
unemployed. Taking opioids may further disrupt the patient's life
and the adverse effects of opioids themselves can become a significant
barrier to patients having an active life, gaining employment, and
sustaining a career.
In addition, lack of employment may be a predictor of aberrant use of
Opioid use may increase accident-proneness. Opioids may increase risk
of traffic accidents and accidental falls.
Rare side effects
Infrequent adverse reactions in patients taking opioids for pain
relief include: dose-related respiratory depression (especially with
more potent opioids), 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). Both
therapeutic and chronic use of opioids can compromise the function of
the immune system. Opioids decrease the proliferation of macrophage
progenitor cells and lymphocytes, and affect cell differentiation (Roy
& Loh, 1996). Opioids may also inhibit leukocyte migration.
However the relevance of this in the context of pain relief is not
Physicians treating patients using opioids in combination with other
drugs keep continual documentation that further treatment is indicated
and remain aware of opportunities to adjust treatment if the patient's
condition changes to merit less risky therapy.
With other depressant drugs
Red line represents the number of benzodiazepine deaths that also
involved opioids, and the purple line represents benzodiazepine deaths
that did not involve opioids.
The concurrent use of opioids with other depressant drugs such as
benzodiazepines or ethanol increases the rates of adverse events and
overdose. As with an overdose of opioid alone, the combination of
an opioid and another depressant may precipitate respiratory
depression often leading to death. These risks are lessened with
close monitoring by a physician, who may conduct ongoing screening for
changes in patient behavior and treatment compliance.
Main article: opioid antagonist
Opioid effects (adverse or otherwise) can be reversed with an opioid
antagonist such as naloxone or naltrexone. These competitive
antagonists bind to the opioid receptors with higher affinity than
agonists but do not activate the receptors. This displaces the
agonist, attenuating or reversing the agonist effects. However, the
elimination half-life of naloxone can be shorter than that of the
opioid itself, so repeat dosing or continuous infusion may be
required, or a longer acting antagonist such as nalmefene may be used.
In patients taking opioids regularly it is essential that the opioid
is only partially reversed to avoid a severe and distressing reaction
of waking in excruciating pain. This is achieved by not giving a full
dose but giving this in small doses until the respiratory rate has
improved. An infusion is then started to keep the reversal at that
level, while maintaining pain relief.
Opioid antagonists remain the
standard treatment for respiratory depression following opioid
overdose, with naloxone being by far the most commonly used, although
the longer acting antagonist nalmefene may be used for treating
overdoses of long-acting opioids such as methadone, and diprenorphine
is used for reversing the effects of extremely potent opioids used in
veterinary medicine such as etorphine and carfentanil. However, since
opioid antagonists also block the beneficial effects of opioid
analgesics, they are generally useful only for treating overdose, with
use of opioid antagonists alongside opioid analgesics to reduce side
effects, requiring careful dose titration and often being poorly
effective at doses low enough to allow analgesia to be maintained.
Opioids bind to specific opioid receptors in the nervous system and
other tissues. There are three principal classes of opioid receptors,
μ, κ, δ (mu, kappa, and delta), although up to seventeen have been
reported, and include the ε, ι, λ, and ζ (Epsilon, Iota, Lambda
and Zeta) receptors. Conversely, σ (Sigma) receptors are no longer
considered to be opioid receptors because their activation is not
reversed by the opioid inverse-agonist naloxone, they do not exhibit
high-affinity binding for classical opioids, and they are
stereoselective for dextro-rotatory isomers while the other opioid
receptors are stereo-selective for levo-rotatory isomers. In addition,
there are three subtypes of μ-receptor: μ1 and μ2, and the newly
discovered μ3. Another receptor of clinical importance is the
opioid-receptor-like receptor 1 (ORL1), which is involved in pain
responses as well as having a major role in the development of
tolerance to μ-opioid agonists used as analgesics. These are all
G-protein coupled receptors acting on GABAergic neurotransmission.
Locants of the morphine molecule
The pharmacodynamic 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. For example, the supraspinal analgesic
properties of the opioid agonist morphine are mediated by activation
of the μ1 receptor; respiratory depression and physical dependence by
the μ2 receptor; and sedation and spinal analgesia by the κ
receptor. Each group of opioid receptors elicits a
distinct set of neurological responses, with the receptor subtypes
(such as μ1 and μ2 for example) providing even more [measurably]
specific responses. Unique to each opioid is its distinct binding
affinity to the various classes of opioid receptors (e.g. the μ, κ,
and δ opioid receptors are activated at different magnitudes
according to the specific receptor binding affinities of the opioid).
For example, the opiate alkaloid morphine exhibits high-affinity
binding to the μ-opioid receptor, while ketazocine exhibits high
affinity to ĸ receptors. It is this combinatorial mechanism that
allows for such a wide class of opioids and molecular designs to
exist, each with its own unique effect profile. Their individual
molecular structure is also responsible for their different duration
of action, whereby metabolic breakdown (such as N-dealkylation) is
responsible for opioid metabolism.
INTA: selective agonist of KOR-DOR and KOR-MOR heteromers. Does not
recruit β-arrestin II. Antinociceptive devoid of aversion, tolerance,
and dependence in mice.
A new strategy of drug development takes receptor signal transduction
into consideration. This strategy strives to increase the activation
of desirable signalling pathways while reducing the impact on
undesirable pathways. This differential strategy has been given
several names, including functional selectivity and biased agonism.
The first opioid that was intentionally designed as a biased agonist
and placed into clinical evaluation is the drug oliceridine. It
displays analgesic activity and reduced adverse effects.
Main article: Equianalgesic
Extensive research has been conducted to determine equivalence ratios
comparing the relative potency of opioids. Given a dose of an opioid,
an equianalgesic table is used to find the equivalent dosage of
another. Such tables are used in opioid rotation practices, and to
describe an opioid by comparison to morphine, the reference opioid.
Equianalgesic tables typically list drug half-lives, and sometimes
equianalgesic doses of the same drug by means of administration, such
as morphine: oral and intravenous.
Binding profiles of opioids at opioid receptors (Ki, nM)
Values are Ki (nM), unless otherwise noted. The smaller the value, the
more strongly the drug binds to the site. Assays were done mostly with
cloned or cultured rodent receptors.
Global estimates of illegal drug users in 2014
(in millions of users)
Opioid prescriptions in the US increased from 76 million in 1991 to
207 million in 2013.
In the 1990s, opioid prescribing increased significantly. Once used
almost exclusively for the treatment of acute pain or pain due to
cancer, opioids are now prescribed liberally for people experiencing
chronic pain. This has been accompanied by rising rates of accidental
addiction and accidental overdoses leading to death. According to the
International Narcotics Control Board, the United States and Canada
lead the per capita consumption of prescription opioids. The
number of opioid prescriptions in the United States and Canada is
double the consumption in the European Union, Australia, and New
Zealand. Certain populations have been affected by the opioid
addiction crisis more than others, including First World
communities and low-income populations. Public health
specialists say that this may result from unavailability or high cost
of alternative methods for addressing chronic pain.
A sample of raw opium
Opioids are among the world's oldest known drugs. Use of the
opium poppy for medical, recreational, and religious purposes can be
traced to the 4th century B.C., when it was used by Sumerians and
Hippocrates wrote about it for its analgesic properties stating;
"Divinum opus est sedare dolores".
In the 19th century morphine was isolated and marketed, and the
hypodermic needle invented, introducing rapid, metered administration
of the primary active compound. Synthetic opioids were
invented, and biological mechanisms discovered in the 20th
Non-clinical use was criminalized in the United States by the Harrison
Narcotics Tax Act of 1914, and by other laws worldwide. Since then,
nearly all non-clinical use of opioids has been rated zero on the
scale of approval of nearly every social institution. However, in
United Kingdom the 1926 report of the Departmental Committee on
Addiction under the Chairmanship of the President
of the Royal College of Physicians reasserted medical control and
established the "British system" of control—which lasted until the
1960s; in the U.S. the
Controlled Substances Act
Controlled Substances Act of 1970 markedly
relaxed the harshness of the Harrison Act.
Before the twentieth century, institutional approval was often higher,
even in Europe and America. In some cultures, approval of opioids was
significantly higher than approval of alcohol.
Opiates were used to
treat depression and anxiety until the mid-1950s.
Society and culture
The term "opioid" originated in the 1950s. It combines "opium" +
"-oid" meaning "opiate-like" ("opiates" being morphine and similar
drugs derived from opium). The first scientific publication to use it,
in 1963, included a footnote stating, "In this paper, the term,
'opioid', is used in the sense originally proposed by George H.
Acheson (personal communication) to refer to any chemical compound
with morphine-like activities". By the late 1960s, research found
that opiate effects are mediated by activation of specific molecular
receptors in the nervous system, which were termed "opioid
receptors". The definition of "opioid" was later refined to refer
to substances that have morphine-like activities that are mediated by
the activation of opioid receptors. One modern pharmacology textbook
states: "the term opioid applies to all agonists and antagonists with
morphine-like activity, and also the naturally occurring and synthetic
opioid peptides". Another pharmacology reference eliminates the
morphine-like requirement: "Opioid, a more modern term, is used to
designate all substances, both natural and synthetic, that bind to
opioid receptors (including antagonists)". Some sources define the
term opioid to exclude opiates, and others use opiate comprehensively
instead of opioid, but opioid used inclusively is considered modern,
preferred and is in wide use.
Efforts to reduce abuse in the US
In 2011, the Obama administration released a white paper describing
the administration's plan to deal with the opioid crisis. The
administration's concerns about addiction and accidental overdosing
have been echoed by numerous other medical and government advisory
groups around the world.
As of 2015, prescription drug monitoring programs exist in every state
but one.[which?] These programs allow pharmacists and prescribers to
access patients’ prescription histories in order to identify
suspicious use. However, a survey of US physicians published in 2015
found that only 53% of doctors used these programs, while 22% were not
aware that the programs were available to them. The Centers for
Disease Control and Prevention was tasked with establishing and
publishing a new guideline, and was heavily lobbied. In 2016, the
Centers for Disease Control and Prevention
Centers for Disease Control and Prevention published its
Guideline for Prescribing Opioids for Chronic Pain, recommending 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
On August 10, 2017,
Donald Trump declared the opioid crisis a
(non-FEMA) national public health emergency.
Morphine and other poppy-based medicines have been identified by the
World Health Organization
World Health Organization as essential in the treatment of severe
pain. As of 2002, seven countries (USA, UK, Italy, Australia, France,
Spain and Japan) use 77% of the world's morphine supplies, leaving
many emerging countries lacking in pain relief medication. The
current system of supply of raw poppy materials to make poppy-based
medicines is regulated by the International Narcotics Control Board
under the provision of the 1961 Single Convention on
The amount of raw poppy materials that each country can demand
annually based on these provisions must correspond to an estimate of
the country's needs taken from the national consumption within the
preceding two years. In many countries, underprescription of morphine
is rampant because of the high prices and the lack of training in the
prescription of poppy-based drugs.
The World Health Organization
The World Health Organization is
now working with administrations from various countries to train
healthworkers and to develop national regulations regarding drug
prescription to facilitate a greater prescription of poppy-based
Another idea to increase morphine availability is proposed by the
Senlis Council, who suggest, through their proposal for Afghan
Afghanistan could provide cheap pain relief solutions
to emerging countries as part of a second-tier system of supply that
would complement the current
INCB regulated system by maintaining the
balance and closed system that it establishes while providing finished
product morphine to those suffering from severe pain and unable to
access poppy-based drugs under the current system.
Opioid use disorder
Opioid use disorder and Recreational drug use
Opioids can produce strong feelings of euphoria and are
frequently used recreationally. Traditionally associated with illicit
opioids such as heroin, prescription opioids are misused
Drug misuse and non-medical use include the use of drugs for reasons
or at doses other than prescribed.
Opioid misuse can also include
providing medications to persons for whom it was not prescribed. Such
diversion may be treated as crimes, punishable by imprisonment in many
countries. In 2014, almost 2 million Americans abused or
were dependent on prescription opioids.
Some humans may be rational in imbibing opioids.
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There are a number of broad classes of opioids:
Natural opiates: alkaloids contained in the resin of the opium poppy,
primarily morphine, codeine, and thebaine, but not papaverine and
noscapine which have a different mechanism of action; The following
could be considered natural opiates: The leaves from Mitragyna
speciosa (also known as kratom) contain a few naturally-occurring
opioids, active via Mu- and Delta receptors. Salvinorin A, found
naturally in the
Salvia divinorum plant, is a kappa-opioid receptor
Esters of morphine opiates: slightly chemically altered but more
natural than the semi-synthetics, as most are morphine prodrugs,
diacetylmorphine (morphine diacetate; heroin), nicomorphine (morphine
dinicotinate), dipropanoylmorphine (morphine dipropionate),
desomorphine, acetylpropionylmorphine, dibenzoylmorphine,
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. Morphine, and
some other opioids, which are produced in small amounts in the body,
are included in this category.
Tramadol and tapentadol, which act as monoamine uptake inhibitors also
act as mild and potent agonists (respectively) of the μ-opioid
receptor. Both drugs produce analgesia even when naloxone, an
opioid antagonist, is administered.
Some minor opium alkaloids and various substances with opioid action
are also found elsewhere, including molecules present in kratom,
Salvia divinorum plants and some species of poppy aside
from Papaver somniferum. There are also strains which produce copious
amounts of thebaine, an important raw material for making many
semi-synthetic and synthetic opioids. Of all of the more than 120
poppy species, only two produce morphine.
Amongst analgesics there are a small number of agents which act on the
central nervous system but not on the opioid receptor system and
therefore have none of the other (narcotic) qualities of opioids
although they may produce euphoria by relieving pain—a euphoria
that, because of the way it is produced, does not form the basis of
habituation, physical dependence, or addiction. Foremost amongst these
are nefopam, orphenadrine, and perhaps phenyltoloxamine or some other
Tricyclic antidepressants have painkilling effect as
well, but they're thought to do so by indirectly activating the
endogenous opioid system.
Paracetamol is predominantly a centrally
acting analgesic (non-narcotic) which mediates its effect by action on
descending serotoninergic (5-hydroxy triptaminergic) pathways, to
increase 5-HT release (which inhibits release of pain mediators). It
also decreases cyclo-oxygenase activity. It has recently been
discovered that most or all of the therapeutic efficacy of paracetamol
is due to a metabolite, AM404, which enhances the release of serotonin
and inhibits the uptake of anandamide.
Other analgesics work peripherally (i.e., not on the brain or spinal
cord). Research is starting to show that morphine and related drugs
may indeed have peripheral effects as well, such as morphine gel
working on burns. Recent investigations discovered opioid receptors on
peripheral sensory neurons. A significant fraction (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 is also blunted by endogenous
opioid peptides activating peripheral opioid receptors.
It was discovered in 1953, that humans and some
animals naturally produce minute amounts of morphine, codeine, and
possibly some of their simpler derivatives like heroin and
dihydromorphine, in addition to endogenous opioid peptides. Some
bacteria are capable of producing some semi-synthetic opioids such as
hydromorphone and hydrocodone when living in a solution containing
morphine or codeine respectively.
Many of the alkaloids and other derivatives of the opium poppy are not
opioids or narcotics; the best example is the smooth-muscle relaxant
Noscapine is a marginal case as it does have CNS effects
but not necessarily similar to morphine, and it is probably in a
category all its own.
Dextromethorphan (the stereoisomer of levomethorphan, a semi-synthetic
opioid agonist) and its metabolite dextrorphan have no opioid
analgesic effect at all despite their structural similarity to other
opioids; instead they are potent
NMDA antagonists and sigma 1 and
2-receptor agonists and are used in many over-the-counter cough
Salvinorin A is a unique selective, powerful ĸ-opioid receptor
agonist. It is not properly considered an opioid nevertheless,
chemically, it is not an alkaloid; and
it has no typical opioid properties: absolutely no anxiolytic or
cough-suppressant effects. It is instead a powerful hallucinogen.
Skeletal molecular images
Opioid-peptides that are produced in the body include:
β-endorphin is expressed in
Pro-opiomelanocortin (POMC) cells in the
arcuate nucleus, in the brainstem and in immune cells, and acts
through μ-opioid receptors. β-endorphin has many effects, including
on sexual behavior and appetite. β-endorphin is also secreted into
the circulation from pituitary corticotropes and melanotropes.
α-neo-endorphin is also expressed in POMC cells in the arcuate
met-enkephalin is widely distributed in the CNS and in immune cells;
[met]-enkephalin is a product of the proenkephalin gene, and acts
through μ and δ-opioid receptors. leu-enkephalin, also a product of
the proenkephalin gene, acts through δ-opioid receptors.
Dynorphin acts through κ-opioid receptors, and is widely distributed
in the CNS, including in the spinal cord and hypothalamus, including
in particular the arcuate nucleus and in both oxytocin and vasopressin
neurons in the supraoptic nucleus.
Endomorphin acts through μ-opioid receptors, and is more potent than
other endogenous opioids at these receptors.
Opium alkaloids and derivatives
Phenanthrenes naturally occurring in (opium):
Preparations of mixed opium alkaloids, including papaveretum, are
still occasionally used.
Esters of morphine
Diacetylmorphine (morphine diacetate; heroin)
Nicomorphine (morphine dinicotinate)
Dipropanoylmorphine (morphine dipropionate)
Ethers of morphine
Semi-synthetic alkaloid derivatives
Levomethadyl Acetate (LAAM)
Loperamide (does cross the blood-brain barrier but is quickly pumped
into the non-central nervous system by P-Glycoprotein. Mild opiate
withdrawal in animal models exhibits this action after sustained and
prolonged use including rhesus monkeys, mice, and rats.)
Plain allosteric modulators do not belong to the opioids, instead they
are classified as opioidergics.
Methylnaltrexone is only peripherally active as it
does not cross the blood-brain barrier in sufficient quantities to be
centrally active. As such, it can be considered the antithesis of
Naloxegol is only peripherally active as it does not cross
the blood-brain barrier in sufficient quantities to be centrally
active. As such, it can be considered the antitheses of loperamide.)
Tables of opioids
Table of morphinan opioids
Table of morphinan opioids: click to
3,6-diesters of morphine
Morphinones and morphols
Active opiate metabolites
Opioid antagonists & inverse agonists
Table of non-morphinan opioids
Table of non-morphinan opioids: click to
Open chain opioids
Beta-amine ketone 'compound 29'
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Opioid Withdrawal Symptoms—Information about
Opioid and opiate
World Health Organization
World Health Organization guidelines for the availability and
accessibility of controlled substances
CDC Guideline for Prescribing Opioids for Chronic
Pain — United
Reference list to the previous publication
Links to all language versions of the previous publication
Opioid side effects (Vimeo) (YouTube)—A short educational
film about the practical management of opioid side effects.
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Opioid receptor agonists (opioids) (e.g., morphine, heroin,
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Nitric oxide prodrugs (e.g., alkyl nitrites (poppers))
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