Each year 69,000 people worldwide die of<unk>  overdose, and 15 million people have an<unk>  addiction. In older adults,<unk>  use is associated with increased adverse effects such as "sedation, nausea, vomiting, constipation, urinary retention, and falls". As a result, older adults taking<unk> s are at greater risk for injury.<unk> s 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. Prescription of<unk> s for acute low back pain and management of osteoarthritis seem to have long-term adverse effects According to the USCDC, methadone was involved in 31% of<unk>  related deaths in the US between 1999–2010 and 40% as the sole drug involved, far higher than other<unk> s. Studies of long term<unk> s have found that many stop them, and that minor side effects were common. Addiction occurred in about 0.3%. In the United States in 2016<unk>  overdose resulted in the death of 1.7 in 10,000 people. In the US charts below many deaths involve multiple<unk> s: File:US timeline.<unk>  deaths.US yearly deaths from all<unk>  drugs. Included in this number are<unk>  analgesics, along with heroin and illicit synthetic<unk> s. File:US timeline. Deaths involving other synthetic<unk> s, predominately Fentanyl.US yearly deaths involving other synthetic<unk> s, predominately Fentanyl. File:US timeline. Prescription<unk>  pain reliever deaths.US yearly deaths involving prescription<unk> s. Non-methadone synthetics is a category dominated by illegally acquired fentanyl, and has been excluded. File:US timeline. Heroin deaths.US yearly overdose deaths involving heroin. Reinforcement disorders Tolerance 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 miosis. Tolerance to<unk> s is attenuated by a number of substances, including: * calcium channel blockers * intrathecal magnesium and zinc * NMDA antagonists, such as dextromethorphan, ketamine, and memantine. * 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<unk> s for extended periods, but does not predict any relationship to misuse or addiction. Physical dependence Physical dependence is the physiological adaptation of the body to the presence of a substance, in this case<unk>  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<unk> s, 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<unk> s over days and weeks can reduce or eliminate the withdrawal symptoms. The speed and severity of withdrawal depends on the half-life of the<unk> ; 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<unk>  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 is poor. Critical patients who received regular doses of<unk> s experience Iatrogenic withdrawal as a frequent syndrome. Addiction Drug addiction is a complex set of behaviors typically associated with misuse of certain drugs, developing over time and with higher drug dosages. Addiction includes psychological compulsion, to the extent that the sufferer persists in actions leading to dangerous or unhealthy outcomes.<unk>  addiction includes insufflation or injection, rather than taking<unk> s orally as prescribed for medical reasons. 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. buprenorphine can also be used together with naloxone for a longer treatment of addiction. / In other European countries including the UK, this is also legally used for OST although on a varying scale of acceptance. Slow-release formulations of medications are intended to curb misuse and lower 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. The amount of evidence available only permits making a weak conclusion, but it suggests that a physician properly managing<unk>  use in patients with no history of substance use disorder can give long-term pain relief with little risk of developing addiction, or other serious side effects. Problems with<unk> s include the following: # Some people find that<unk> s do not relieve all of their pain. # Some people find that<unk> s side effects cause problems which outweigh the therapy's benefit # Some people build tolerance to<unk> s 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<unk>  use can cause<unk> -induced hyperalgesia, which is a condition in which the patient has increased sensitivity to pain. All of the<unk> s can cause side effects. Common adverse reactions in patients taking<unk> s for pain relief include nausea and vomiting, drowsiness, itching, dry mouth, dizziness, and constipation. 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<unk>  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<unk> s 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) Evidence suggests that<unk> -inclusive anaesthesia is associated with postoperative nausea and vomiting. Patients with chronic pain using<unk> s had small improvements in pain and physically functioning and increased risk of vomiting. Drowsiness Tolerance to drowsiness usually develops over 5–7 days, but if troublesome, switching to an alternative<unk>  often helps. Certain<unk> s 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 generally effective. * Stimulants (e.g. caffeine, modafinil, amphetamine, methylphenidate) Itching Itching tends not to be a severe problem when<unk> s 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<unk>  induced drowsiness. However, some sedating antihistamines such as orphenadrine can produce a synergistic pain relieving effect permitting smaller doses of<unk> s be
Opioid
Heroin
Synthetic cannabinoids
Nicotine
Phencyclidine
Cocaine 
Cocaine
Benzphetamine