Opioid

An opioid is any psychoactive chemical that resembles morphine or other opiates in its pharmacological effects. Opioids work by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract. The receptors in these organ systems mediate both the beneficial effects and the side effects of opioids.

Although the term opiate is often used as a synonym for opioid, the term opiate is properly limited to the natural alkaloids found in the resin of the opium poppy (Papaver somniferum), while opioid refers to both opiates and synthetic substances, as well as to opioid peptides.

Opioids are among the world's oldest known drugs; the therapeutic use of the opium poppy predates recorded history. The analgesic (painkiller) effects of opioids are due to decreased perception of pain, decreased reaction to pain as well as increased pain tolerance. The side effects of opioids include sedation, respiratory depression, constipation, and a strong sense of euphoria. Opioids can cause cough suppression, which can be both an indication for opioid administration or an unintended side effect. Opioid dependence can develop with ongoing administration, leading to a withdrawal syndrome with abrupt discontinuation. Opioids are not only well known for their addictive properties, but also for their ability to produce a feeling of euphoria, motivating some to use opioids recreationally.

Medical uses

Opioids have long been used to treat acute pain (such as post-operative pain).^[1] They have also been found to be invaluable in palliative care to alleviate the severe, chronic, disabling pain of 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 in chronic cancer pain. However, opioids should be used cautiously in chronic non-cancer pain.^[2]

Opioids for pain relief are also used when nondrug pain treatment options including cognitive behavioral therapy, exercise, spinal manipulation, and physical medicine and rehabilitation programs are insufficient to meet therapy goals.^[3] Patients taking opioids talk with their health care provider to develop a personal health plan which includes a combination of therapies, perhaps including drug and nondrug treatments, to relieve pain.^[3]

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.^[3][4] Some types of chronic pain, including the pain caused by fibromyalgia or migraine, are preferentially treated with drugs other than opioids.^[3][5][6] The efficacy of using opioids to lessen chronic neuropathic pain is uncertain.^[7]

Opioids such as Nalbuphine have also been used to relieve labor pain during Childbirth.^[8]

Contraindications

Opioids are contraindicated as a first-line treatment for headache because they impair alertness, bring risk of dependence and addiction, and increase the risk that episodic headaches will become chronic.^[9] Opioids also can cause heightened sensitivity to headache pain.^[9] 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.^[9]

Opioids are sometimes used 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.^[2] 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.^[3] Chronic pain which occurs only periodically, such as that from nerve pain, migraines, and fibromyalgia, frequently is better treated with drugs other than opioids.^[3][5] Acetaminophen and non-steroidal anti-inflammatory drugs including ibuprofen and naproxen are common and safer alternatives or complements to opioids.^[3]

Safety

Studies have shown opioids to be safe when they are used correctly and in the ways that are well understood.^[10]

Carefully titrating the dose of opioids can provide for effective pain relief while minimizing adverse effects. Morphine and diamorphine have been shown to have a wider therapeutic range or "safety margin" than some other opioids. It is impossible to tell which patients need low doses and which need high doses, so all have to be started on low doses, unless changing from another strong opioid.^[11]

Opioid analgesics do not cause any specific organ toxicity, unlike many other drugs, such as aspirin and acetaminophen. They are not associated with upper gastrointestinal bleeding and renal toxicity.^[12]

In older adults, opioid use is associated with increased adverse effects such as "sedation, nausea, vomiting, constipation, urinary retention, and falls".^[13] As a result older adults taking opioids are at greater risk for injury.^[14]

There are gaps in available research describing the safe use of opioids long-term or comparing the relative safety of the long-term use of various opioids to each other.^[3] The research also does not have information about the extent to which opioids differ in terms of the risk they bring for causing addiction.^[3]

Research suggests that when methadone is used long-term use it can build-up unpredictably in the body and lead to potentially deadly slowed breathing.^[3][15][16] Regular physician monitoring reduces the likelihood of problems.^[3][15]

According to a cohort study, the rate of opioid related death was 0.017% per year amongst patients prescribed opioids for non-cancer pain from 1997-2005 in Washington State. Increasing dose and age were found to correlate with increased risk of overdose.^[17] While a cohort study is a higher level of evidence than case-control, a case-control study done in Canada correlates well as it had an opioid related death rate of 0.024% per year amongst patients prescribed opioids for non-cancer pain over a 10-year period.^[18]

Tolerance

Tolerance to opioids may occur. In spite of tolerance, the dose required to achieve analgesia can level off for many months at a time, depending on severity of pain, which varies.^{[citation needed]}

High doses are not necessarily required to control the pain of advanced or end-stage disease.^{[citation needed]}

Tolerance is a process characterized by neuroadaptations that result in reduced drug effects. While receptor downregulation may often play an important role other mechanisms are also known.^[19] 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 miosis.^[20]

Tolerance to opioids is attenuated by a number of substances, including:

• calcium channel blockers^[21][22]

• intrathecal magnesium^[23] and zinc^[24]

• NMDA antagonists, such as dextromethorphan, ketamine,^[25] and memantine.^[26]

• cholecystokinin antagonists, such as proglumide^[27][28][29]

• Newer agents such as the phosphodiesterase inhibitor ibudilast have also been researched for this application.^[30]

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 addiction.

Dependence is characterised by unpleasant withdrawal symptoms that occur if opioid use is abruptly discontinued. The withdrawal symptoms for opiates 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 will reduce or eliminate the withdrawal symptoms.^[11] The speed and severity of withdrawal depends on the half-life of the opioid; heroin and morphine withdrawal occur more quickly and are more severe 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.^[31] Physical dependence does not predict drug misuse or true addiction, and is closely related to the same mechanism as tolerance.

Addiction

Addiction is the process whereby physical and psychological dependence develops to any drug—including opioids. This tends to occur over time or with higher doses of substances. Withdrawal symptoms can reinforce the addiction, driving the user to continue taking the drug despite negative consequences of behavior. Psychological addiction is more common in people insufflating or injecting opioids recreationally, rather than taking them orally as prescribed for medical reasons.^[11]

In European nations such as Austria, Bulgaria, and Slovakia, slow release oral morphine formulations are used in opiate substitution therapy 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 of acceptance.

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 FDA.^[32][33]

Adverse effects

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 can give long-term pain relief with little risk of developing addiction, abuse, or other serious side effects.^[10]

Problems with opioids include the following:

1. Some people find that opioids do not relieve all of their pain.^[3][35]
2. Some people find that opioids side effects cause problems which outweigh the therapy's benefit^[3][10]
3. 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.^[3][10]
4. Long-term opioid use can cause opioid-induced hyperalgesia, which is a condition in which the patient has increased sensitivity to pain.^[3][36]

All of the opioids can cause side effects.^[3][34] Common adverse reactions in patients taking opioids for pain relief include nausea and vomiting, drowsiness, itching, dry mouth, dizziness, and constipation.^[3][11][34]

When prescribing an opioid, physicians have a process to recommend the correct one, find the right dosage for the patient, and then minimize the side effects.^[3]

Nausea

Tolerance to nausea occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol once at night) are very effective.^{[citation needed]} Due to severe side effects such as tardive dyskinesia, haloperidol is currently rarely used. A related drug, Compazine (prochlorperazine) is more often used, although it has similar risks. Stronger antiemetics such as ondansetron or tropisetron may be indicated if nausea is severe or continues for an extended period, although these tend to be avoided due to their high cost unless nausea is really problematic. A cheaper alternative is dopamine antagonists, e.g. domperidone and metoclopramide. Domperidone does not cross the blood–brain barrier, so blocks opioid emetic action in the chemoreceptor trigger zone without adverse central anti-dopaminergic effects (not available in the U.S.) Some antihistamines with anti-cholinergic properties (e.g. orphenadrine or diphenhydramine) may also be effective. The first-generation anti-histamine hydroxyzine is very commonly used, with the added advantages of not causing movement disorders, and also possessing analgesic-sparing properties.

• 5-HT₃ antagonists (e.g. ondansetron)
• Dopamine antagonists (e.g. domperidone)
• Anti-cholinergic antihistamines (e.g. diphenhydramine)

Vomiting

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 10 mg every eight hours). 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)

Drowsiness

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. Treatment is at any rate possible—CNS stimulants are generally effective.

• Stimulants (e.g. caffeine, modafinil, amphetamine, methylphenidate)

Itching

Itching tends not to be a severe problem when opioids are used for pain relief, but if required then antihistamines are useful for counteracting itching. Non-sedating antihistamines such as fexofenadine are preferable so as to avoid increasing opioid induced drowsiness, although some sedating antihistamines such as orphenadrine may be helpful as they produce a synergistic analgesic effect which allows smaller doses of opioids to be used while still producing effective analgesia. For this reason some opioid/antihistamine combination products have been marketed, such as Meprozine (meperidine/promethazine) and Diconal (dipipanone/cyclizine), which may also have the added advantage of reducing nausea as well.

• Antihistamines (e.g. fexofenadine)

Constipation

Constipation develops in many people on opioids and since tolerance to this problem does not develop readily, most patients on long-term opioids will need a laxative.^[37] Over 30 years experience in palliative care has shown that most opioid constipation can be successfully prevented: "Constipation … is treated [with laxatives and stool-softeners]" (Burton 2004, 277). According to Abse, "It is very important to watch out for constipation, which can be severe" and "can be a very considerable complication" (Abse 1982, 129) if it is ignored. Peripherally acting opioid antagonists such as alvimopan (Entereg) and methylnaltrexone (Relistor) have been found to effectively relieve opioid induced constipation without triggering withdrawal symptoms, although alvimopan is contraindicated in patients who have taken opioids for more than seven days, is only FDA-approved for 15 doses or less, and may increase risk of heart attack.^[38][39] For mild cases, a lot of water (around 1.5 L/day) and fiber might suffice (in addition to the laxative and stool-softeners).

• Stool-softening and peristalsis-promoting laxatives (e.g. docusate in combination with bisacodyl or senna).
• Peripherally-acting opioid antagonists (e.g. methylnaltrexone) effectively prevent constipation while not affecting centrally mediated analgesia or provoking withdrawal syndrome, however these can still potentially reduce the efficacy of opioid analgesics in the treatment of conditions where much of the pain relief comes from action at peripherally situated opioid receptors, such as in inflammatory conditions like arthritis or post-surgical pain.
• High water intake and dietary fiber

For more severe and/or chronic cases, the drugs that are used work by not increasing peristalsis, but by preventing water uptake in the intestine, leading to a softer stool with a larger component of water, and, additionally, by acidifying the environment inside the intestine, which both decreases water uptake and enhances peristalsis (e.g. lactulose, which is controversially noted as a possible probiotic). The following drugs are generally efficacious:

• Polyethylene glycol 3350±10% dalton powder for solution (MiraLax, GlycoLax).
• Lactulose syrup

One combination, oxycodone/naloxone, aims to reduce systemic side effects by combining oxycodone with an opioid suppressor, naloxone, in a form which does not pass through the blood–brain barrier. Thus, the constipation effect is suppressed, but not the pain reduction.

Respiratory depression

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.^[40][41] Newer drugs such as BIMU-8 and CX-546 may however be much more effective.^[42][43][44]

• 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-HT_1A agonists such as 8-OH-DPAT and repinotan also counteract opioid-induced respiratory depression, but at the same time reduce analgesia, which limits their usefulness for this application.
• Opioid antagonists (e.g. naloxone, nalmefene, diprenorphine)

Hyperalgesia

Opioid-induced hyperalgesia has been observed in some patients, whereby individuals using opioids to relieve pain may paradoxically experience more pain as a result of their medication. This phenomenon, although uncommon, is seen in some palliative care patients, most often when dose is escalated rapidly.^[45][46] If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia.^[47][48]

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, BD-1047 or (+)-Naloxone respectively.^{[49][50][51][52]} 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 addition of a supplemental non-opioid analgesic), rotating between different opioid drugs, or by switching to a milder opioid with mixed mode of action that also counteracts neuropathic pain, particularly tramadol or tapentadol.^{[53][54][55][56]}

• NMDA antagonists such as ketamine
• SNRIs such as milnacipran
• anticonvulsants such as gabapentin or pregabalin

Increased mortality

Oxycodone and codeine may double mortality as compared to hydrocodone.^[57] In contrast to hydrocodone, codeine is metabolized by cytochrome P-450 CYP2D6, which may lead to variable pharmacokinetics due to single-nucleotide polymorphisms and drug interactions. Although oxycodone is metabolized by CYP2D6, it only accounts for a minor portion, whereas CYP3A4 plays a greater role; thus clinically oxycodone metabolism is rarely affected by variants in single-nucleotide polymorphisms.^[58]

Hormone imbalance

Clinical studies have consistently associated medical and recreational opioid use with hypogonadism and hormone imbalance in both genders. 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 their agonism of opioid receptors in the hypothalamus and the pituitary gland. A study conducted on heroin addicts found that their testosterone levels returned to normal within one month of abstinence, suggesting that the effect is temporary. As of 2013, the effect of low-dose or acute opiate use on the endocrine system is unclear.^[59][60]

Disruption of work

Use of opioids may be a risk factor for failing to return to work.^[61][62]

In addition, lack of employment may be a predictor of aberrant use of prescription opioids.^[63]

People who take opioids long term have increased likelihood of being unemployed.^[64] Taking opioids further disrupts 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.^[3]

Increased accident-proneness

Opioid use may increase accident-proneness. Opioids may increase risk of traffic accidents^[65][66] and accidental falls.^[67]

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).^[11] 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 known.

Interactions

The concurrent use of opioids with benzodiazepines or alcohol increases the rates of adverse events, overdose, and death in patients.^[3][68] These risks are lessened with close monitoring by a physician, who may conducting ongoing screening for changes in patient behavior and treatment compliance.^[68] 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.^[68] When opioids are combined with sedatives then the patient has increased risk of breathing problems.^[69]

Opioid antagonist

Finally, opioid effects (adverse or otherwise) can be reversed with an opioid antagonist such as naloxone or naltrexone.^[70] These competitive antagonists bind to the opioid receptors with higher affinity than agonists but do not activate the receptors. This displaces the agonist, attenuating and/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.

Pharmacology

Opioid comparison

Drug	Relative Potency[71]	Nonionized Fraction	Protein Binding	Lipid Solubility[72]
Morphine	1	++	++	++
Meperidine	0.1	+	+++	++
Hydromorphone	10
Alfentanil	10–25	++++	++++	+++
Fentanyl	75–125	+	+++	++++
Remifentanil	250	+++	+++	++
Sufentanil	500–1000	++	++++	++++
Etorphine	1000–3000

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 laevo-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.

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^{[citation needed]}. 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.

Functional selectivity

A new strategy of drug development takes receptor signal transduction into consideration. The strategy strives to increase activation of desirable, and to reduce impact on undesirable, signalling 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 a chemical compound with the code number TRV130. It displays analgesic activity and reduced adverse effects.^[73]

Opioid comparison

Extensive research has been conducted to determine equivalence ratios comparing the relative potency of opioids. Given a dose of an opioid, an equianalgesic chart is used to find the equivalent dosage of another.

History

Non-clinical use was criminalized in the U.S 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 Morphine and Heroin 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 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.^[74]

Society and culture

Global shortages

Morphine and other poppy-based medicines have been identified by the World Health Organization as essential in the treatment of severe pain. However, only six countries use 77% of the world's morphine supplies, leaving many emerging countries lacking in pain relief medication.^[75] 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 Narcotic Drugs. 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 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 medicines.^[76]

Another idea to increase morphine availability is proposed by the Senlis Council, who suggest, through their proposal for Afghan Morphine, that 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.

United States approval

The sole clinical indications for opioids in the United States, according to Drug Facts and Comparisons, 2005, are:

• Moderate to severe pain, i.e., to provide analgesia or, in surgery, to induce and maintain anesthesia, as well as allaying patient apprehension right before the procedure. Fentanyl, oxymorphone, hydromorphone, and morphine are most commonly used for this purpose, in conjunction with other drugs such as scopolamine, short and intermediate-acting barbiturates, and benzodiazepines, especially midazolam which has a rapid onset of action and shorter duration than diazepam (Valium) or similar drugs. The enhancement of the effects of each drug by the others is useful in troublesome procedures like endoscopies, complicated and difficult deliveries (pethidine and its relatives and piritramide where it is used are favoured by many practitioners with morphine and derivatives as the second line), incision & drainage of severe abscesses, intraspinal injections, and minor and moderate-impact surgical procedures in patients unable to have general anesthesia due to allergy to some of the drugs involved or other concerns.
• Cough (codeine, dihydrocodeine, ethylmorphine (dionine), hydromorphone and hydrocodone, with morphine or methadone as a last resort.)
• Diarrhea (generally loperamide, difenoxin or diphenoxylate; but paregoric, powdered opium or laudanum or morphine may be used in some cases of severe diarrheal diseases, e.g. cholera); also diarrhea secondary to Irritable Bowel Syndrome (Codeine, paregoric, diphenoxylate, difenoxin, loperamide, laudanum)
• Anxiety due to shortness of breath (oxymorphone and dihydrocodeine only)
• Opioid dependence (methadone and buprenorphine only)

Evidence supports the use of low dose, regular oral opioids for the safe relief of breathlessness that is not responsive to disease-modifying treatments. This action appears to be a result of the effect on opioid receptors in the limbic system.

Opioids are not used for psychological relief.

Opioids are often used in combination with adjuvant analgesics (drugs which have an indirect effect on the pain). In palliative care, opioids are not recommended for sedation or anxiety because experience has found them to be ineffective agents in these roles. Some opioids are relatively contraindicated in renal failure because of the accumulation of the parent drug or their active metabolites (e.g. codeine and oxycodone). Age (young or old) is not a contraindication to strong opioids. Some synthetic opioids such as pethidine have metabolites which are actually neurotoxic and should therefore be used only in acute situations.

Recreational use

Drug misuse is the use of drugs for reasons other than what the drug was prescribed for. Opioids are primarily misused due to their ability to produce euphoria. Misuse can also include giving drugs to people for whom it was not prescribed or selling the medication, both of which are crimes punishable by imprisonment in some, if not most, countries.

Classification

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 agonist.
• 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, diacetyldihydromorphine;^[77]
• 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 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.
• There are also drugs such as tramadol and tapentadol that are chemically not of the opioid class, but do have agonist actions at the μ-opioid receptor. Although their exact mechanism of action is not fully understood, they both have a dual mode of action, the second mode of action appearing to be on the noradrenergic and serotonergic systems.^[78] This second mechanism of action was discovered during testing in where the drugs showed signs of analgesia even when naloxone, an opioid antagonist, was administered.^[79]

Some minor opium alkaloids and various substances with opioid action are also found elsewhere, including molecules present in kratom, Corydalis, and 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 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 and/or some other antihistamines. 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, making paracetamol a prodrug) which enhances the release of serotonin and also interacts as with the cannabinoid receptors by inhibiting the uptake of anandamide.^{[citation needed]}

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.^[80] 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.^[81] Inflammatory pain is also blunted by endogenous opioid peptides activating peripheral opioid receptors.^[82]

It has been discovered in 1953,^{[citation needed]} that the human body, as well as those of some other animals, naturally produce minute amounts of morphine and codeine and possibly some of their simpler derivatives like heroin and dihydromorphine, in addition to the well known 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 papaverine. 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 suppressants.
Salvinorin A is a unique selective, powerful ĸ-opioid receptor agonist. It is not properly considered an opioid nevertheless, because:

1. chemically, it is not an alkaloid; and
2. it has no typical opioid properties: absolutely no anxiolytic or cough-suppressant effects. It is instead a powerful hallucinogen.

Opioid peptides	Skeletal molecular images
Adrenorphin
Amidorphin
Casomorphin
DADLE
DAMGO
Dermorphin
Endomorphin
Morphiceptin
Nociceptin
Octreotide
Opiorphin
TRIMU 5

Table of morphinan opioids

Table of morphinan opioids: click to

Morphine 2,4-Dinitrophenylmorphine 6-MDDM Chlornaltrexamine Desomorphine Dihydromorphine Hydromorphinol Methyldesorphine N-Phenethylnormorphine RAM-378 3,6-diesters of morphine Acetylpropionylmorphine Dihydroheroin Dibenzoylmorphine Dipropanoylmorphine Heroin Nicomorphine Codeine-dionine family Codeine 6-MAC Benzylmorphine Codeine methylbromide Dihydroheterocodeine Ethylmorphine Heterocodeine Pholcodine Myrophine Morphinones and morphols 14-Cinnamoyloxycodeinone 14-Ethoxymetopon 14-Methoxymetopon PPOM 7-Spiroindanyloxymorphone Acetylmorphone Codeinone Conorphone Codoxime Thebacon Hydrocodone Hydromorphone Metopon Morphinone N-Phenethyl-14-Ethoxymetopon Oxycodone Oxymorphone Pentamorphone Semorphone Various semi-synthetics Chloromorphide 14-Hydroxydihydrocodeine Acetyldihydrocodeine Dihydrocodeine Nalbuphine Nicocodeine Nicodicodeine Oxymorphazone 1-Iodomorphine Active opiate metabolites M6G 6-MAM Norcodeine Normorphine Morphine-N-oxide Synthetic morphinans Cyclorphan DXA Levorphanol Levophenacylmorphan Levomethorphan Norlevorphanol Oxilorphan Phenomorphan Furethylnorlevorphanol Xorphanol Butorphanol Cyprodime Drotebanol Orvinols & Oripavine derivatives 7-PET Acetorphine BU-48 Buprenorphine Cyprenorphine Dihydroetorphine Etorphine Norbuprenorphine Opioid antagonists & inverse agonists 5'-Guanidinonaltrindole Diprenorphine Levallorphan MNTX Nalfurafine Nalmefene Naloxazone Naloxone Nalorphine Naltrexone Naltriben Naltrindole 6β-Naltrexol-d4 Morphinan dimers Pseudomorphine Naloxonazine Norbinaltorphimine

Table of non-morphinan opioids

Table of non-morphinan opioids: click to

Benzomorphans 8-CAC Alazocine Bremazocine Dezocine Ketazocine Metazocine Pentazocine Phenazocine Cyclazocine 4-Phenylpiperidines 4-Fluoromeperidine Allylnorpethidine Anileridine Benzethidine Carperidine Difenoxin Diphenoxylate Etoxeridine Furethidine Hydroxypethidine Morpheridine Oxpheneridine Pethidine Pheneridine Phenoperidine Piminodine Properidine Sameridine Allylprodine α-Meprodine MPPP PEPAP α-Prodine Prosidol Trimeperidine Acetoxyketobemidone Droxypropine Ketobemidone Methylketobemidone Propylketobemidone Alvimopan Loperamide Picenadol Open chain opioids Dipipanone Methadone Normethadone Phenadoxone Dimepheptanol Levacetylmethadol Dextromoramide Levomoramide Racemoramide Diethylthiambutene Dimethylthiambutene Ethylmethylthiambutene Piperidylthiambutene Pyrrolidinylthiambutene Thiambutene Tipepidine Dextropropoxyphene Dimenoxadol Dioxaphetyl butyrate Levopropoxyphene Norpropoxyphene Diampromide Phenampromide Propiram Methiodone Isoaminile Lefetamine R-4066 Anilidopiperidines 3-Allylfentanyl 3-Methylfentanyl 3-Methylthiofentanyl 4-Phenylfentanyl Alfentanil α-Methylacetylfentanyl α-Methylfentanyl α-Methylthiofentanyl β-Hydroxyfentanyl β-Hydroxythiofentanyl β-Methylfentanyl Brifentanil Carfentanil Fentanyl Lofentanil Mirfentanil Ocfentanil Ohmefentanyl Parafluorofentanyl Phenaridine Remifentanil Sufentanil Thiofentanyl Trefentanil Various others Ethoheptazine Metheptazine Metethoheptazine Proheptazine Bezitramide Piritramide Clonitazene Etonitazene 18-MC 7-Hydroxymitragynine Akuammine Eseroline Hodgkinsine Mitragynine Pericine BW373U86 DPI-221 DPI-287 DPI-3290 SNC-80 AD-1211 AH-7921 Azaprocin Bromadol BRL-52537 Bromadoline C-8813 Ciramadol Doxpicomine Enadoline Faxeladol GR-89696 Herkinorin ICI-199441 ICI-204448 J-113397 JTC-801 LPK-26 Methopholine MT-45 NDMC NNC 63-0532 Nortilidine O-Desmethyltramadol Prodilidine Profadol Ro64-6198 SB-612111 SC-17599 RWJ-394674 TAN-67 Tapentadol Tifluadom Tramadol Trimebutine U-50488 U-69593 Viminol W-18 Alvimopan JDTic MCOPPB

See also

• Froehde reagent
• Opiate comparison

References

External links

• Opioid Withdrawal Symptoms—Information about Opioid and opiate withdrawal issues
• World Health Organization guidelines for the availability and accessibility of controlled substances
• Reference list to the previous publication
• Links to all language versions of the previous publication
• Video: Opioid side effects (Vimeo) (YouTube)—A short educational film about the practical management of opioid side effects.

v t e Opioids Opium and poppy straw derivatives Crude opiate extracts / whole opium products B&O Supprettes Diascordium Dover's powder Kendal Black Drop Laudanum Mithridate Opium Paregoric Polish heroin (compote/kompot) Poppy straw Poppy tea Smoking opium Theriac Natural opiates Opium alkaloids Codeine Morphine Oripavine Pseudomorphine Thebaine Alkaloid salts mixtures Pantopon Papaveretum (Omnopon) Semisynthetics including Bentley compounds Morphine family 2,4-Dinitrophenylmorphine 6-MDDM Azidomorphine Chlornaltrexamine Desocodeine Desomorphine Dihydromorphine Hydromorphinol Methyldesorphine N-Phenethylnormorphine RAM-378 3,6-diesters of morphine Acetylpropionylmorphine Diacetyldihydromorphine Dibenzoylmorphine Dipropanoylmorphine Heroin Nicomorphine Codeine-dionine family 6-Monoacetylcodeine Benzylmorphine Codeine methylbromide Ethylmorphine Heterocodeine Isocodeine Myrophine Pholcodine Morphinones and morphols 14-Cinnamoyloxycodeinone 14-Ethoxymetopon 14-Methoxymetopon 14-Phenylpropoxymetopon 3-Acetyloxymorphone 3,14-Diacetyloxymorphone 6-MDDM 7-Spiroindanyloxymorphone Acetylmorphone Codeinone Codoxime Conorfone Hydrocodone Hydromorphone IBNtxA Methyldihydromorphine Metopon Morphinone N-Phenethyl-14-ethoxymetopon Nalmexone Oxycodone Oxymorphol Oxymorphone Pentamorphone Semorphone Thebacon Morphides α-Chlorocodide Chloromorphide Dihydrocodeine series 14-Hydroxydihydrocodeine Acetyldihydrocodeine Dihydrocodeine Nicocodeine Nicodicodeine Nitrogen morphine derivatives Codeine-N-oxide Morphine-N-oxide Hydrazones Oxymorphazone Halogenated morphine derivatives 1-Iodomorphine Active opiate metabolites 6-Monoacetylmorphine Morphine-6-glucuronide Norcodeine Normorphine Morphinans 3-Hydroxymorphinan Butorphanol Cyclorphan Cyprodime Dextrallorphan Drotebanol Ketorfanol Levallorphan Levomethorphan Levophenacylmorphan Levorphanol Nalbuphine Norlevorphanol Oxilorphan Phenomorphan Proxorphan Racemethorphan/Methorphan Racemorphanol/Morphanol Ro4-1539 Sinomenine/Cocculine Xorphanol Benzomorphans 8-CAC Alazocine Anazocine Bremazocine Butinazocine Carbazocine Cogazocine Dezocine Eptazocine Etazocine Ethylketazocine Fluorophen Ibazocine Ketazocine Metazocine Moxazocine Pentazocine Phenazocine Tonazocine Volazocine Zenazocine 4-Phenylpiperidines Pethidines (Meperidines) 4-Fluoropethidine Allylnorpethidine Anileridine Benzethidine Carperidine Difenoxin Diphenoxylate Etoxeridine (Carbetidine) Furethidine Hydroxypethidine (Bemidone) Morpheridine Oxpheneridine (Carbamethidine) Pethidine (Meperidine) Pethidine intermediate A Pethidine intermediate B (Norpethidine) Pethidine intermediate C (Pethidinic Acid) Pheneridine Phenoperidine Piminodine Properidine (Ipropethidine) Sameridine Prodines Allylprodine Meprodine (α-meprodine / β-meprodine) MPPP (Desmethylprodine) PEPAP Prodine (α-prodine / β-prodine) Prosidol Trimeperidine (Promedol) Ketobemidones Acetoxyketobemidone Droxypropine Ketobemidone Methylketobemidone Propylketobemidone Others Alvimopan Loperamide Picenadol Open chain opioids Amidones Dipipanone Isomethadone Levomethadone Methadone Normethadone Norpipanone Phenadoxone (Heptazone) Methadols Acetylmethadol Alphacetylmethadol Alphamethadol Betacetylmethadol Betamethadol Dimepheptanol (methadol) Isomethadol Levacetylmethadol Noracymethadol Moramides Desmethylmoramide Dextromoramide Levomoramide Moramide/Racemoramide Thiambutenes Diethylthiambutene Dimethylthiambutene Ethylmethylthiambutene Piperidylthiambutene Pyrrolidinylthiambutene Tipepidine Phenalkoxams Dextropropoxyphene Dimenoxadol Dioxaphetyl butyrate Levopropoxyphene Norpropoxyphene Ampromides Diampromide Phenampromide Propiram Others Alimadol IC-26 Isoaminile Lefetamine R-4066 Anilidopiperidines 3-Allylfentanyl 3-Methylfentanyl 3-Methylthiofentanyl 4-Phenylfentanyl α-Methylacetylfentanyl α-Methylfentanyl α-methylthiofentanyl β-hydroxyfentanyl β-hydroxythiofentanyl β-methylfentanyl Alfentanil Brifentanil Carfentanil Fentanyl Lofentanil Mirfentanil Ocfentanil Ohmefentanyl Parafluorofentanyl Phenaridine Remifentanil Sufentanil Thiofentanyl Trefentanil Oripavine derivatives 7-PET Acetorphine Alletorphine BU-48 Buprenorphine Cyprenorphine Dihydroetorphine Etorphine Homprenorphine Norbuprenorphine Phenazepanes Ethoheptazine Meptazinol Metethoheptazine Metheptazine Proheptazine Pirinitramides Bezitramide Piritramide Benzimidazoles Clonitazene Etonitazene Indoles 18-MC 7-Hydroxymitragynine Akuammine Eseroline Hodgkinsine Ibogaine Mitragynine Noribogaine Pericine Diphenylmethyl- piperazines BW373U86 DPI-221 DPI-287 DPI-3290 SNC-80 Opioid peptides Adrenorphin Amidorphin Biphalin Casokefamide Casomorphin Cytochrophin DADLE DAMGO Deltorphin Dermorphin Dynorphin Endomorphin Endorphins Enkephalin Frakefamide Gliadorphin Hemorphin Leumorphin Metkefamide Morphiceptin Neoendorphin Nociceptin Octreotide Opiorphin Rubiscolin Spinorphin TRIMU 5 Tynorphin Valorphin Others AD-1211 AH-7921 Azaprocin BRL-52537 Bromadol Bromadoline C-8813 Ciprefadol Ciramadol Doxpicomine Enadoline Ethanol Faxeladol GR-89696 Herkinorin ICI-199,441 ICI-204,448 J-113,397 JTC-801 LPK-26 MCOPPB Metofoline MT-45 N-Desmethylclozapine NNC 63-0532 Nortilidine O-Desmethyltramadol Phenadone Phencyclidine Prodilidine Profadol Ro64-6198 Salvinorin A SB-612,111 SC-17599 RWJ-394,674 TAN-67 Tapentadol Tifluadom Tilidine Tramadol Trimebutine U-50,488 U-69,593 Viminol W-18 Opioid antagonists & inverse agonists 5'-Guanidinonaltrindole Alvimopan Chlornaltrexamine Chloroxymorphamine Conorfone Cyclazocine Cyprodime Diacetylnalorphine Difenamizole Diprenorphine (M5050) Gemazocine JDTic Levallorphan LY-255,582 Methylnaltrexone Nalbuphine Naldemedine Nalmefene Nalmexone Nalorphine Nalorphine dinicotinate Naloxazone Naloxegol Naloxonazine Naloxone Naltrexol-d4 Naltrexone Naltriben Naltrindole Norbinaltorphimine Oxilorphan Quadazocine Samidorphan Tonazocine Zenazocine Biased ligands TRV130 Herkinorin 6'-GNTI Uncategorized opioids Anilopam Asimadoline Axomadol FE 200665 Fedotozine Nalfurafine Nalorphine Nalorphine dinicotinate SoRI-9409 List of opioids

v t e Analgesics (N02A, N02B) Opioids See also: Opioids template Opium & alkaloids thereof Codeine# Morphine# Opium Laudanum Paregoric Semi-synthetic opium derivatives Acetyldihydrocodeine Benzylmorphine Buprenorphine Desomorphine Diacetylmorphine Dihydrocodeine Dihydromorphine Ethylmorphine Hydrocodone Hydromorphinol Hydromorphone Nicocodeine Nicodicodeine Nicomorphine Oxycodone Oxymorphone Synthetic opioids Alphaprodine Anileridine Butorphanol Dextromoramide Dextropropoxyphene Dezocine Fentanyl Ketobemidone Levorphanol Meptazinol Methadone Nalbuphine Pentazocine Pethidine Phenazocine Piminodine Piritramide Propiram Tapentadol Tilidine Tramadol Pyrazolones Ampyrone / Aminophenazone Metamizole Phenazone Propyphenazone Cannabinoids Ajulemic acid AM404 Cannabidiol Cannabis Nabilone Nabiximols Tetrahydrocannabinol Anilides Paracetamol (acetaminophen)# Phenacetin Propacetamol Non-steroidal anti-inflammatories See also: NSAIDs template Propionic acid class Fenoprofen Flurbiprofen Ibuprofen# Ketoprofen Naproxen Oxaprozin Oxicam class Meloxicam Piroxicam Acetic acid class Diclofenac Indometacin Ketorolac Nabumetone Sulindac Tolmetin COX-2 inhibitors Celecoxib Lumiracoxib Parecoxib Rofecoxib Valdecoxib Anthranilic acid (fenamate) class Meclofenamic acid Mefenamic acid Salicylates Aspirin (Acetylsalicylic acid)# (+paracetamol/caffeine) Benorylate Diflunisal Ethenzamide Magnesium salicylate Salicin Salicylamide Salsalate Trisalate Wintergreen (Methyl salicylate) Atypical, adjuvant and potentiators, metabolic agents and miscellaneous Amitriptyline# Befiradol Bicifadine Camphor Carisoprodol Chlorzoxazone Cimetidine Clonidine Cyclobenzaprine Duloxetine Esreboxetine Flupirtine Gabapentin Gabapentin enacarbil Glafenine Hydroxyzine Ketamine Menthol Mephenoxalone Methocarbamol Methoxyflurane Nefopam Orphenadrine Pregabalin Proglumide Scopolamine Tebanicline Trazodone Ziconotide #WHO-EM ‡Withdrawn from market Clinical trials: †Phase III §Never to phase III M: CNS anat (n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug (N1A/2AB/C/3/4/7A/B/C/D)

v t e Euphoriants Cannabinoids AM-2201 JWH-018 THC (found in Cannabis) UR-144 Depressants General Barbiturates Benzodiazepines GHB Methaqualone Pregabalin Z-drugs Alcohols 2M2B Ethanol drinking alcohol Ethchlorvynol Methylpentynol UMB68 Opioids 7-Hydroxymitragynine (Kratom) Buprenorphine Codeine Dipipanone Fentanyl Heroin Heterocodeine Hydromorphone Methadone Morphine Opium Oxycodone Oxymorphone Pethidine Drugs with mixed mechanism of actions (MoA) Cocaine Dimethyltryptamine (DMT) Ibogaine Methadone Pentazocine Tramadol Stimulants General Nicotine (found in Tobacco) Releasing agents (RA) 4-Methylaminorex Amphetamine MDMA Mephedrone Methamphetamine Methylone Reuptake inhibitors (RI) Cocaine Ethylphenidate Methylphenidate Hallucinogens Deliriants Atropine Cyclizine Diphenhydramine Orphenadrine Scopolamine Trihexyphenidyl Dissociatives Dextromethorphan (DXM) Ketamine (K) Methoxetamine (MXE) Nitrous oxide (N2O) Phencyclidine (PCP) Psychedelics 2C-B 2C-I DMT LSD Mescaline Psilocybin