Opioid

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

An opioid is a chemical substance that has a morphine-like action in the body. The main use is for pain relief. These agents work by binding to opioid receptors, which are found principally in the central nervous system and the gastrointestinal tract. The receptors in these two organ systems mediate both the beneficial effects, and the undesirable side effects. There are a number of broad classes of narcotics:

• natural opiates, alkaloids contained in the resin of the opium poppy including morphine, codeine, thebaine, and oripavine;
• semi-synthetic opiates, created from the natural opioids, such as hydromorphone, hydrocodone, oxycodone, and heroin;
• fully synthetic opioids, such as fentanyl, pethidine, methadone, and propoxyphene;
• endogenous opioid peptides, produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphins.

Although the term opiate is often used as a synonym for opioid, it is more properly limited to the natural opium alkaloids and the semi-synthetics derived from them.

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 morbid seek orientation, habituation, physical dependence, or addiction. Foremost amongst these are nefopam, orphenadrine, and perhaps phenyltoloxamine and/or some other antihistamines. The remainder of analgesics work peripherally. Research is starting to show that morphine and related drugs may indeed have peripheral effects as well, such as morphine gel working on burns, but peripherally-acting analgesics include aspirin, paracetamol, ibuprofen and the like.

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.

Finally, some opioids such as diphenoxylate do not possess analgesic action, narcotic or otherwise.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Opioid-peptides that are produced in the body include:

• Endorphins
• Enkephalins
• Dynorphins
• Endomorphins

β-endorphin is expressed in Pro-opiomelanocortin (POMC) cells in the arcuate nucleus and in a small population of neurons in the brainstem, 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-neoendorphin is also expressed in POMC cells in the arcuate nucleus.

[met]-enkephalin is widely distributed in the CNS; [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.

Phenanthrenes naturally occurring in opium:

• Codeine
• Morphine
• Thebaine
• Oripavine^[1]

Preparations of mixed opium alkaloids, including papaveretum, are still occasionally used.

• Diacetylmorphine (heroin)
• Dihydrocodeine
• Hydrocodone
• Hydromorphone
• Nicomorphine
• Oxycodone
• Oxymorphone

• Fentanyl
• Alphamethylfentanyl
• Alfentanil
• Sufentanil
• Remifentanil
• Carfentanyl
• Ohmefentanyl

• Pethidine (meperidine)
• Ketobemidone
• MPPP
• Allylprodine
• Prodine
• PEPAP

• Propoxyphene
• Dextropropoxyphene
• Dextromoramide
• Bezitramide
• Piritramide
• Methadone
• Dipipanone
• Levo-alphacetylmethadol (LAAM)
• Loperamide (used for diarrhoea, does not cross the blood-brain barrier)
• Diphenoxylate (used for diarrhoea, does not appreciably cross the blood-brain barrier)

• Pentazocine
• Phenazocine

• Buprenorphine
• Etorphine

• Butorphanol
• Nalbuphine
• Levorphanol
• Levomethorphan

• Dezocine
• Lefetamine
• Meptazinol
• Tilidine
• Tramadol
• Tapentadol

• Nalmefene
• Naloxone
• Naltrexone

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Opioids bind to specific opioid receptors in the central nervous system and in 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, lamda and zeta) receptors. σ (sigma) receptors are no longer considered to be opioid receptors as they are not reversed by naloxone, exhibit high-affinity binding for ketamine and phencyclidine and are stereoselective for dextro-rotatory isomers while the other opioid receptors are stereo-selective for laevo-rotatory isomers. In addition, there are two subtypes of μ receptor: μ₁ and μ₂. 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 on which receptor 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 (dependency) by the μ₂ receptor, and sedation and spinal analgesia by the κ receptor.

There are four major subtypes of opioid receptors:^[1]

Receptor	Subtypes	Location[2][3]	Function[2][3]
delta (δ) DOR OP1 (I)	δ1, δ2	Brain Pontine nuclei Amygdala Olfactory bulbs deep Cortex Peripheral sensory neurons	Analgesia Antidepressant effects Convulsant effects Physical dependence Perhaps of mu-opioid receptor-mediated respiratory depression
kappa (κ) KOR OP2 (I)	κ1, κ2, κ3	Brain Hypothalamus Periaqueductal gray Claustrum Spinal cord substantia gelatinosa Peripheral sensory neurons	Analgesia Anticonvulsant effects Dissociative & Deliriant effects Diuresis Dysphoria Miosis Neuroprotection Sedation
mu (μ) MOR OP3 (I)	μ1, μ2, μ3	Brain Cortex (laminae III and IV) Thalamus striosomes Periaqueductal gray Rostral ventromedial medulla Spinal cord substantia gelatinosa Peripheral sensory neurons Intestinal tract	μ1: Analgesia Physical dependence μ2: Respiratory depression Miosis Euphoria Reduced GI motility Physical dependence μ3: Possible vasodilation
Nociceptin receptor NOP OP4	ORL1	Brain cortex Amygdala Hippocampus Septal nuclei Habenula Hypothalamus Spinal cord	Anxiety Depression Appetite Development of tolerance to μ agonists

(I). Name based on order of discovery

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Opioids have long been used to treat acute pain (such as post-operative pain). They have also found to be invaluable in palliative care to alleviate the severe, chronic, disabling pain of terminal conditions such as cancer. Contrary to popular belief, high doses are not required to control the pain of advanced or end-stage disease, with the median dose in such patients being only 15mg oral morphine every four hours (90mg/24 hours), i.e. 50% of patients manage on lower doses. In recent years there has been an increased use of opioids in the management of non-malignant chronic pain. This practice has grown from over 30 years and has become a serious problem.

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

• Analgesia and anesthesia
• Cough (codeine and hydrocodone only)
• Diarrhoea (generally loperamide or diphenoxylate, but laudanum or morphine may be used in some cases of severe diarrheal diseases)
• Anxiety due to shortness of breath (oxymorphone only)
• Detoxification (methadone and buprenorphine only)

In the U.S., doctors virtually never prescribe opioids for psychological relief (with the narrow exception of anxiety due to shortness of breath), despite their extensively reported psychological benefits. There are virtually no exceptions to this practice, even in circumstances where researchers have reported opioids to be especially effective and where the possibility of addiction or diversion is very low—for example, in the treatment of senile dementia, geriatric depression, and psychological distress due to chemotherapy or terminal diagnosis (see Abse; Berridge; Bodkin; Callaway; Emrich; Gold; Gutstein; Mongan; Portenoy; Reynolds; Takano; Verebey; Walsh; Way).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Opioid analgesics may cause more drug toxicity, at least in geriatrics, than non-selective inhibitors of cyclooxygenase (non-steroidal anti-inflammatory agents) or cyclooxygenase 2 inhibitors.^[1]

Oxycodone and codeine may increase mortality relative to codeine and hydrocodone^[2] and may cause more drug toxicity in geriatrics than codeine or hydrocodone.^[2] In contrast to hydrocodone, oxycodone and codeine and metabolized by cytochrome P-450 CYP2D6 which may lead to variable pharmacokinetics due to single-nucleotide polymorphisms and drug interactions.^[3]

Opioid analgesics, with long-term use, 80% of patients may have drug toxicity, most commonly gastrointestinal. In addition, substance abuse and “aberrant medication-taking behaviors” may occur.^[4]

Serious drug toxicity from long-term use may be low according to one systematic review.^[5]

These include: nausea and vomiting, drowsiness, dry mouth, miosis, and constipation. Fortunately, most of these are not a problem (see Treating Opioid Adverse Effects below).

These include: dose-related respiratory depression (see below), 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).

Opioid use may be associated with gastroparesis^[6], possibly via stimulation of μ (MOP; β-endorphin) and maybe δ (DOP; enkephalin) receptors.

Codeine may be more likely to affect the gastrointestinal tract^[7].

Buprenorphine, a partial agonist at the μ receptor, has also been reported to cause gastroparesis^[8].

The affect of tramadol is not clear^[9].

Treatment may include sympatholyic medications such as acute phentolamine or chronic clonidine^[10].

Chronic opioids may cause male hypogonadism.^[11][12]

Use of opioids may be a risk factor for failing to return to work.^[13][14]

In addition, lack of employment may be a predictor of aberrant use of prescription opioids.^[15]

Opioids may increase risk of traffic accidents^[16] and accidental falls^[17].

Opioid-induced hyperalgesia is a phenomenon associated with the long term use of opioids such as morphine, hydrocodone, oxycodone, and methadone. 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. ^{[18] [19]} If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia. ^{[20] [21]}

In a small study of patients on chronic opioids, about half had sleep disorders^[22]:

• daytime hypercapnia
• average apnea-hypopnea index (AHI) 33

Death from overdose on opioids may be more common than traffic accidents in the United States.^[23] The rate of overdose is increasing faster among women and men according to the Centers for Disease Controll.^[24]

Chronic use of the equivalent of more than 20 mg/day of morphine may lead to unintentional or intentional overdose.^[25]

Overdose may be more common with with doses equivalent to more than 100 mg/day of morphine.^[26] Overdose may^[27] or may not^[26] be increased with long acting opioids.

In veterinary medicine, there is a maximum effective analgesic dose of buprenorphine, although the frequency of administration may usefully be increased.^[28]

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.

Most adverse effects can be managed successfully. (For more complete information see ^[29] and the online palliative care formulary available on Palliativedrugs.com.)

Nausea: tolerance occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol 1.5–3mg once at night) are very effective.

Vomiting: if this is due to gastric stasis (large volume vomiting, brief nausea relieved by vomiting, oesophageal reflux, epigastric fullness, early satiation) then this can be managed with a prokinetic (e.g. domperidone or metoclopramide 10mg every eight hours), but usually needs to be started by a non-oral route (e.g. subcutaneous for metoclopramide, rectally for domperidone).

Drowsiness: tolerance usually develops over 5–7 days, but if troublesome, switching to an alternative opioid often helps.

Constipation: this develops in 99% of patients on opioids and since tolerance to this problem does not develop, nearly all patients on opioids will need a laxative. 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.

Respiratory depression: Although this is the most serious adverse reaction associated with opioid use it usually is seen with the use of a single, intravenous dose in an opioid-naive patient. In patients taking opioids regularly for pain relief, tolerance to respiratory depression occurs rapidly, so that it is not a clinical problem.

Reversing the effect of opioids: Opioid effects can be rapidly 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 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. 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 (e.g. naloxone 400 microg) but giving this in small doses (e.g. naloxone 40 microg) until the respiratory rate has improved. An infusion is then started to keep the reversal at that level, while maintaining pain relief.

There are a number of paradoxical beliefs about opioids:

• 33% of UK doctors believe they had possibly shortened life during alleviation of symptoms,^[30] and yet a follow-up study showed that UK doctors are particularly cautious about shortening life.^[31]
• There is a belief that the use of opioids in pain is a fine balance between relief and hastening death, and yet palliative care physicians do not find themselves faced with the dilemma of relieving symptoms at the risk of shortening life.^[32]
• The Dutch public equate high dose morphine and sedation with euthanasia,^[33] and yet it is the least used class of drug used for euthanasia in the Netherlands.

However, studies around the globe over the past 20 years have repeatedly shown opioids to be safe when they are used correctly. In the UK two studies have shown that double doses of bedtime morphine did not increase overnight deaths,^[34] and that sedative dose increases were not associated with shortened survival (n=237).^[35] Another UK study showed that the respiratory rate was not changed by morphine given for breathlessness to patients with poor respiratory function (n=15).^[36] In Australia, no link was found between doses of opioids, benzodiazepines or haloperidol and survival.^[37] In Taiwan, a study showed that giving morphine to treat breathlessness on admission and in the last 48 hours did not affect survival.^[38] The survival of Japanse patients on high dose opioids and sedatives in the last 48 hours was the same as those not on such drugs.^[39] In U.S. patients whose ventilators were being withdrawn, opioids did not speed death, while benzodiazepines resulted in longer survival (n=75).^[40] Morphine given to elderly patients in Switzerland for breathlessness showed no effect on respiratory function (n=9, randomised controlled trial).^[41] Injections of morphine given subcutaneously to Canadian patients with restrictive respiratory failure did not change their respiratory rate, respiratory effort, arterial oxygen level, or end-tidal carbon dioxide levels.^[42] Even when opioids are given intravenously, respiratory depression is not seen.^[43]

• Starting doses: a person who has never been on analgesics would be started on oral morphine 2.5–5mg every four hours (or morphine by injection 1–2.5mg every four hours). Higher doses can be used if the patient was already on weaker analgesics.

• Titration: this describes the adjustment of a drug dose to a patient, while allowing the patient’s body time to adjust to the drug to minimise adverse effects. Titration is done in 25–50% steps every 1–2 days.

• Safety margin of opioids: morphine and diamorphine have a wide safety margin or “therapeutic range”.

• Dose range: this is very wide but usually lies between 30–500mg per 24 hours of oral morphine, but with a median of 90mg (or 15mg every four hours). 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.^[44]

• When discontinuing opioids in tolerant users, a taper of buprenorphine over 4 weeks may be used.^[45]

The principle of double effect is not used in palliative care. Doctors are not faced with the dilemma of giving a potentially lethal drug dose to a distressed patient.^[46]

A palliative care doctor gives repeated, small doses of one or more drugs, each titrated to an individual until the symptoms are eased, while doing everything possible to avoid toxicity. Doctors who give 30–60 times the required dose of morphine or diamorphine, usually as a single intravenous dose, are acting either negligently or maliciously. Since drug records should exist for opioids, there is a clear audit trail to follow if a subsequent investigation is required.

With exceptions such as Shipman, UK doctors are very cautious about shortening life.^[47] The persistent belief that opioids and sedatives shorten life or hasten death stems from the experiences of bad practice in the use of the drugs. Evidence in the last 20 years has shown that opioids and sedatives are safe when following palliative care protocols. Clinicians who believe otherwise should be challenged to provide robust clinical evidence to support their view.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] Delband Yekta Moazami, M.D.[3]

Synonyms and keywords: Opioid use disorder

Opioid use disorder(OUD) is defined as a loss of control over opioid use leading to physical, psychological, and social consequences. With chronic use for treatment of pain, dependence may lead to substance abuse and “aberrant medication-taking behaviors” may occur.^[1] From 2000-2005, the abuse of prescribed opiods, especially oxycodone extended release (OxyContin) and hydrocodone, has increased.^[2]

Opioid use disorder(OUD) is defined as a loss of control over opioid use leading to physical, psychological, and social consequences. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) includes diagnostic criteria for OUD that are universal across all drugs and are based on the presence of at least two of 11 criteria organized into four clusters: 1-Impaired control 2-Social impairment 3- Risky use 4- Pharmacologic dependence^[3] Opioid abuse happens for different of reasons, including self-medication, use for reward, compulsive use due to addiction, and diversion for profit. treatment methods that balance chronic pain while reducing the risks for drug abuse, misuse, and distraction are strongly needed.^[4][5]

Tolerance is the process whereby neuroadaptation occurs (through receptor desensitization) resulting in reduced drug effects. Tolerance is more pronounced for some effects than for others – tolerance occurs quickly to the effects on mood, itching, urinary retention, and respiratory depression, but occurs more slowly to the analgesia and other physical side effects. Impaired control leads to the use in bigger amounts or for longer periods of time than anticipated; persistent desire to reduce or stop use; many unsuccessful attempts to reduce or stop use; a significant amount of time spent using or recovering from the effects of the substance; a strong urge to use or crave the substance.^[3]

Tolerance to opioids is attenuated by a number of substances, including calcium channel blockers^[6][7], intrathecal magnesium^[8] and zinc^[9], and NMDA antagonists such as ketamine.^[10]

Magnesium and zinc deficiency speed up the development of tolerance to opioids and relative deficiency of these minerals is quite common^[11] due to low magnesium/zinc content in food and use of substances which deplete them including diuretics (such as alcohol, caffeine/theophylline) and smoking. Reducing intake of these substances and taking zinc/magnesium supplements may slow the development of tolerance to opiates.

Dependence is characterized by extremely unpleasant withdrawal symptoms that occur if opioid use is abruptly discontinued after tolerance has developed. The withdrawal symptoms include severe dysphoria, sweating, nausea, rhinorrhea, depression, severe fatigue, vomiting and pain. Slowly reducing the intake of opioids over days and weeks will reduce or eliminate the withdrawal symptoms.^[12] The speed and severity of withdrawal depend on the half-life of the opioid — heroin and morphine withdrawal occur more quickly and are more severe than methadone withdrawal, but methadone withdrawal takes longer. 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 also be treated with other medications, but with low efficacy.^[13]

Addiction is the process whereby physical and/or psychological addiction develops to a drug – including opioids. The withdrawal symptoms can reinforce the addiction, driving the user to continue taking the drug. Psychological addiction is more common in people taking opioids recreationally, it is rare in patients taking opioids for pain relief.^[14]

Drug abuse is the misuse of drugs producing negative consequences.

• Depressive disorder
• Alcohol intoxication
• Sedative, hypnotic,or anxiolytic intoxication
• Sedative-hypnotic withdrawal
• Hallucinogen intoxication
• Stimulant intoxication^[15]

The 12 month prevalence of opioid use disorder is 370 per 100,000 (0.37%) in ages 18 years and older in the community population.^[15] In 2016, an estimated 26.8 million persons worldwide with OUD, up 47.3 percent from 1990. The highest prevalence was found in high-income North America, North Africa, and the Middle East.^[16]

Variability in opioid prescribing in emergency departments is a risk factor.^[17][18] The Centers for Disease Control and Prevention has studied risk factors^[19]. Substance use disorders are linked to psychiatric problems; those who have one are more likely to have the other. Substance use causing mental diseases, people with psychiatric disorders using substances to manage symptoms, and common risk factors for both conditions are all possible explanations. The lifetime prevalence of comorbid psychiatric disorders in patients with OUD has been found to range between 24 and 86 percent, with mood and anxiety disorders being the most common axis I disorders and antisocial personality disorder being the most commonly diagnosed axis II condition. Determining whether a person has a substance-induced disorder or a basic psychiatric disorder can be difficult in people with co-occurring disorders.^[20][21]

“

A. A problematic pattern of opioid use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period: 1. Opioids are often taken in larger amounts or over a longer period than was intended. 2. There is a persistent desire or unsuccessful efforts to cut down or control opioid use. 3. A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects. 4. Craving, or a strong desire or urge to use opioids. 5. Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, or home. 6. Continued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids. 7. Important social, occupational, or recreational activities are given up or reduced because of opioid use. 8. Recurrent opioid use in situations in which it is physically hazardous. 9. Continued opioid use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance. 10. Tolerance, as defined by either of the following: a. A need for markedly increased amounts of opioids to achieve intoxication or desired effect. b. A markedly diminished effect with continued use of the same amount of an opioid. Note: This criterion is not considered to be met for those taking opioids solely under appropriate medical supervision. 11. Withdrawal, as manifested by either of the following: a. The characteristic opioid withdrawal syndrome. b. Opioids (or a closely related substance) are taken to relieve or avoid withdrawal symptoms. Note: This criterion is not considered to be met for those individuals taking opioids solely under appropriate medical supervision . Specify if: In early remission: After full criteria for opioid use disorder were previously met, none of the criteria for opioid use disorder have been met for at least 3 months but for less than 12 months (with the exception that Criterion A4, “Craving, or a strong desire or urge to use opioids,” maybe met). In sustained remission: After full criteria for opioid use disorder were previously met, none of the criteria for opioid use disorder have been met at any time during a period of 12 months or longer (with the exception that Criterion A4, “Craving, or a strong desire or urge to use opioids,” maybe met). Specify if: On maintenance therapy: This additional specifier is used if the individual is taking a prescribed agonist medication such as methadone or buprenorphine and none of the criteria for opioid use disorder have been met for that class of medication (except tolerance to, or withdrawal from, the agonist). This category also applies to those Individuals being maintained on a partial agonist, an agonist/antagonist, or a full antagonist such as oral naltrexone or depot naltrexone. In a controlled environment: This additional specifier is used if the individual is in an environment where access to opioids is restricted.

”

There are several ways to test for unhealthy drug abuse. one of the simplest is to ask two questions:

• 1. In the last 12 months, how many days have you used drugs other than alcohol? ( a score of seven or more considered as positive)
• 2. In the last 12 months, how many days have you used medicines more than you intended? (it is positive if two or more are positive)

These two questions were proved to be more than 90% sensitive and specific for drug use disorder in a study of over 1200 primary care patients.^[22]

• Psychosocial treatment

several methods of psychosocial interventions such as individual counseling or group therapy can benefit people with OUD. Clinicians in primary care can assist patients who are interested in these treatments in getting connected to them. there is limited evidence to recommend these kinds of interventions either alone or in combination with pharmacotherapy. Most of the surveys on these therapeutic interventions are used in conjunction with medication.^[23][24]

• Pharmacotherapy

long-term(maintenance) medication is still the first-line treatment for patients with OUD, and many patients prefer it. the evidence for the three medications that have been approved for the treatment of OUD- Methadone, Buprenorphine, Naltrexone– will be discussed in the following section. long-term maintenance therapy with agonists is the mainstay treatment for OUD.^[25] a systematic review of 19 cohort studies in 2017 showed that pharmacotherapy with methadone and buprenorphine significantly reduces mortality for all reasons in the patients using opioid agonist comparing to the people without medical treatment.^[26]

• Buprenorphine

Buprenorphine is a highly effective long-acting partial opioid agonist for the treatment of OUD. Buprenorphine is available in different formulations in the USA. Most of them are combined with naloxone to avoid injection or intranasal use. sublingual tablets are available in 2, and 8 mg doses with or without naloxone. many patients may need doses above 16mg/day up to 32 mg. for those who do not respond to 32mg/day of buprenorphine, methadone therapy should be considered. long term maintenance treatment with buprenorphine is more effective than short-term or medically supervised withdrawal treatment.^[27] Buprenorphine has a high tendency to bind to the receptor, which adds to its safety. however it can dislodge other narcotics and lead to unwanted withdrawal if given too soon after using an agonist.^[28] to prevent this buprenorphine should be started when withdrawal symptoms begin in the patient. usually, after 8 to 12 hours of using short-acting opioids such as heroin, buprenorphine can be started with a low dose.^[29]

• Methadone

Methadone is a highly effective long-acting agonist, which noticeably reduces the use of illicit opioid use.^[25]. considering that methadone has a long half-life, the starting dose is at 30-40 mg/day and increases slowly until an effective therapeutic dose is reached. The goal and effective dose are to suppress opioid craving and at the same time to avoid over-sedation. The studies show that higher doses of methadone( doses of at least 60-100 mg) are linked with maintaining treatment and reduction of overdose mortality.^[30]

• Naltrexone

Naltrexone is an opium antagonist, the newest medication for the treatment of OUD in primary care settings. The oral form has low efficacy. However, RCT studies have shown that the monthly injection of the intramuscular extended-release formulation is superior to the placebo and the oral form of naltrexone and reduces craving and relapse in patients with OUD.^[31][32]

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Synonyms and keywords: Opioid intoxication

An opioid overdose is an acute condition due to excessive use of narcotics. It should not be confused with opioid dependency. Prescription opioid overdose was responsible for more deaths in the United States from 1999-2008 than heroin or cocaine overdose combined.^[1] Heroin overdose in a number of cases, can occur accidentally in a group of people called as ‘body packers‘ and ‘body stuffers‘. Body packers swallow bags of heroin, to hide them in their gastrointestinal tract. While body stuffers, usually stuff their rectum or vagina with bags of heroin in an attempt to illegally smuggle them into a country. Since these bags are not specially designed to store drug in the body, there are chances that they might actually rupture leading to accidental poisoning/overdose.^[2][3][4][5]

As per recent Center for disease control (CDC) data, it accounts for the largest percentage of substance abuse deaths in prescription drug category. Of the 22,134 deaths relating to prescription drug overdose in 2010, 16,651 (75%) involved opioid analgesics (also called opioid pain relievers or prescription painkillers), and 6,497 (30%) involved benzodiazepines.^[6] In the year 2011, the most commonly involved drug was cocaine, with 162.1 visits per 100,000 population. This was closely followed by marijuana, which was involved in 146.2 visits per 100,000 population. Other drugs had lower rates: heroin (83.0 visits per 100,000 population), illicit stimulants (predominately amphetamines and methamphetamine; 51.3 visits per 100,000 population), and other illicit drugs (predominately PCP and various hallucinogens; 42.1 visits per 100,000 population).^[7]

Although any opioid can by abused for recreational purposes, some of the most common ones are as follows:
For a more detailed description of one of these opioids click on the name.

• Heroin
• Morphine
• Oxycodone/oxycontin
• Buprenorphine
• Dextromethorphan
• Fentanyl
• Hydrocodone
• Meperidine
• Methadone
• Propoxyphene
• Tramadol

Opioid overdoses associated with a conjunction of benzodiazepines or alcohol use leads to a contraindicated condition wherein higher instances of general negative overdose traits native to the overdose profile of opioid use alone but to a much greater extent.^[8][9] Other CNS depressants, or “downers”, muscle relaxers, pain relievers, anti-convulsants, anxiolytics (anti-anxiety drugs), treatment drugs of a psychoactive or epileptic variety or any other such drug with its active function meant to calm or mitigate neuronal signaling (barbiturates, etc.) can additionally cause a worsened condition with less likelihood of recovery cumulative to each added drug of a diverse or disparate hampering effect to the central or peripheral nervous system of the user. This includes drugs less immediately classed to a slowing of the metabolism such as with GABAergics like GHB or glutamatergic antagonists like PCP or Ketamine.

Disease/Condition	Differentiating feature
Alcohol intoxication	Altered mental status without miosis and respiratory depression.
Sedative hypnotics	Miosis absent.
Phencyclidine (PCP) overdose	CNS depression and miosis are present. Nystagmus present and respiratory depression absent.
Ketamine overdose	CNS depression and miosis are present. Nystagmus present and respiratory depression absent.
Antipsychotic overdose	Hypotension and bradycardia are seen, but other features are absent.
Pontine hemorrhage	Miosis present, other features absent.
Gammahydroxybutyrate/gammabutyrolactone overdose	Most likely manifests as opioid overdose. Miosis may not be present.
Clonidine/imidazolines overdose	Profound bradycardia and hypotension.

Additionally, none of these have a response to naloxone, as dramatic as in treating opioid overdose.

Heroin is a semisynthetic derivative of morphine, that has a high addictive potential. When used intravenously, it is even more potent. Similar to morphine and other analgesic opioids, heroin has mu, kappa, and delta receptor activity. Stimulation of the mu receptors results in analgesia, euphoria, CNS depression, respiratory depression, and miosis.^[10]

Opioids can cause respiratory depression, due to their role in reducing brains response to changes in PaCO₂ levels and hypoxia. Respiratory arrest is the most common cause of death in cases of opioid overdose. The effect on respiratory depression is more potent for pure agonists such as heroin and morphine, as compared to partial agonists such as burenorphine. It can also cause a mild hypotension by reducing the sympathetic tone in blood vessels, leading to vasodilation and facial flushing. opioids have inhibitory effects on baroreceptors as well as reduces gastric motility, leading further to bradycardia and constipation respectively.^[10]

The onset of action, peak effects, and duration of action vary with the different methods of use, as well as the type of opioid used. On injecting, the onset of action is within 1-2 minutes when injected intravenous and within 15-30 minutes when injected intramuscular or snorted. Analgesic effects usually last for 3-5 hours.

Heroin is rapidly converted to 6-monoacetylmorphine (6-MAM) by the liver, brain, heart, and kidneys, which is further converted to morphine. Morphine has a longer half life as compared to heroin. However a small amount of 6-MAM is detectable in urine for a long time, which serves as the basis for its detection in toxicology screens.^[11]

Several factors are thought to increase the risk of opioid overdose in a patient abusing these agents. These are described below:^[12][13]

Demographic factors: Being a young, single male, without a stable employment is a high risk factor for overdose.

Resuming the behavior after a period of abstinence: The abstinence could be due to voluntary efforts to stop the abuse, medically induced withdrawal or imprisonment resulting in forced abstinence.

Inconsistency with the quality of the drugs: Most commonly these are sold on streets, the quality being unpredictable & inconsistent. A higher purity sample may cause overdose at doses to which the person was used to before.

Mixing different type of drugs: Mixing drugs that have a brain and respiratory function depressing action similar to opioids, may lead to an overdose even at smaller doses. This may include drugs such as sedative-hypnotic (diazepam, clonazepam, lorazepam etc), H1 antihistaminics such as chlorpheniramine or promethazine or even alcohol. Different drugs will potentiate the effect of opioids differently.^{[14] [15]}

Physical illness or recent infections: During states of metabolic stress, especially when a person is severely ill or dehydrated, even smaller doses may cause overdose.

Mental health: A person suffering from mental illnesses such as depression, schizophrenia or bipolar disorder may use opioid overdose as a means of committing suicide.

Past overdose events: Recent research has shown that people who have overdosed in the past are at much greater risk of future overdose.

“

A. Recent use of an opioid. AND B. Clinically significant problematic behavioral or psychological changes (e.g., initial euphoria followed by apathy, dysphoria, psychomotor agitation or retardation, impaired judgment) that developed during, or shortly after, opioid use. AND C. Pupillary constriction (or pupillary dilation due to anoxia from severe overdose) and one (or more) of the following signs or symptoms developing during, or shortly after, opioid use: 1. Drowsiness or coma. 2. Slurred speech. 3. Impairment in attention or memory. AND D. The signs or symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication with another substance. Specify if: With perceptual disturbances: This specifier may be noted in the rare instance in which hallucinations with intact reality testing or auditory, visual, or tactile illusions occur in the absence of a delirium.

”

Opiate overdose symptoms and signs include: decreased level of consciousness and pinpoint pupils.^[17] Heart rate and breathing slow down, sometimes to a stop. Blue lips and nails are caused by insufficient oxygen in the blood. Other symptoms include seizures and muscle spasms. A person experiencing an opiate overdose usually will not wake up even if their name is called or if they are shaken vigorously. The following list summarizes the most commonly experienced symptoms with opioid overdose.^[18]

• Airways and lungs

• No breathing
• Shallow breathing
• Slow and difficult breathing

• Eyes, ears, nose, and throat

• Dry mouth
• Miosis (Extremely small pupils ‘pinpoint pupils’)
• Tongue discoloration

• Heart and blood

• Low blood pressure
• Weak pulse

• Skin

• Bluish-colored nails and lips (cyanosis)
• Compartment syndrome

• Stomach and intestines

• Constipation
• Spasms of the stomach and intestinal tract

• Nervous system

• Coma
• Delirium
• Disorientation
• Drowsiness
• Muscle spasticity
• Stupor

• Renal system

• Myoglobinuric renal failure

Naloxone is very effective at reversing the cause, rather than just the symptoms, of an opioid overdose.^[19] A longer-acting variant is naltrexone. Naltrexone is primarily meant to treat opioid and alcohol dependence. Diprenorphine (Revivon) is similar in action to naloxone, only it is significantly stronger and is reserved for acting as an antagonist to the strongest, non-human opioids, such as carfentanyl (in fact, carfentanyl, and other opioids for usage on large animals such as elephants, often come packaged with Revivon to be used after carfentanyl is no longer needed in the animal).

Initial adult dose for patient experiencing respiratory depression is 0.04 mg IV, while the initial pediatric dose is 0.1 mg/Kg IV. If the respiratory rate doesn’t increase in next 2-3 minutes a second dose of 0.5 mg is given. If further there is no increase in respiratory rate, following doses can be administered after every 2-3 minutes till an increase in respiratory rate is obtained, 2 mg, 4 mg, 10 mg, 15 mg.

Shown below is a management protocol for treating opioid overdose.^[20]

Opioid overdose: Respiratory rate < 12/min

Oxygenate with bag and mask, administer naloxone with a gradually increasing dose till reversal of respiratory depression is seen

History of use of morphine, fentanyl or other long acting opioids?

Yes

No

Admit to ICU

Observe for 4-6 hours after last naloxone dose

Patient fully awake and alert ?

No

Yes

Perform intubation, begin a continuous naloxone infusion

Admit to ICU

Continue infusion till respiratory depression reversed, observe 4-6 hours after naloxone infusion is stopped

Discharge patient, when awake & alert with stable vital signs

Intra-nasal administration: In recent years, there has been an emphasis on studying the efficacy of intra-nasal administration of naloxone, to treat opioid overdose in community. The studies have all converged to the fact that, the efficacy and safety are comparable to other routes of administration, that it is likely to reduce blood exposure in paramedics and can be successfully given even by bystanders.^{[21] [22] [23]}

The U.S. Centers for Disease Control and Prevention (CDC) estimates that US programs for drug users and their caregivers prescribing take-home doses of naloxone and training on its utilization are estimated to have reversed 10,000 opioid overdose deaths.^[24][25] Healthcare institution-based naloxone prescription programs have also helped reduce rates of opioid overdose in the US state of North Carolina, and have been replicated in the US military.^[26][27] Nevertheless, scale-up of healthcare-based opioid overdose interventions is limited by providers’ insufficient knowledge and negative attitudes towards prescribing take-home naloxone to prevent opioid overdose.^[28] Programs training police and fire personnel in opioid overdose response using naloxone have also shown promise in the US.^[29][30]

Although opioid overdose accounts for the leading cause of accidental death, it can be prevented and often in primary care settings.^[31][32] Providers should routinely screen patients using tools such as the CADE-AID and the Drug Abuse Screening Test (DAST-10) to screen adults and the CRAFT to screen adolescents aged 14–18 years.^[31] Other “drug seeking” behaviors as well as physical indications of drug use should be used as clues to perform formal screenings.^[31] Individuals diagnosed with opioid dependence should be prescribed naloxone to prevent overdose and/or should be directed to one of the many intervention/treatment options available, such as needle exchange programs and treatment centers.^[31][32] Brief motivational interviewing can also be performed by the clinician during patient visits and has been shown to improve patient motivation to change their behavior.^[31][33] Despite these opportunities, the dissemination of prevention interventions in the US has been hampered by the lack of coordination and sluggish federal government response.^[32]

Philip Seymour Hoffman (2014), Anna Nicole Smith (2007), Anna Nicole Smith (1999), River Phoenix (1993), Heath Ledger (2008), Janis Joplin (1970), Corey Haim (2010), Whitney Houston (2012), John Belushi (1982), Chris Farley (1997), Elvis Presley (1977), Judy Garland (1969), Hillel Slovak (1988), Jimi Hendrix (1969), Paula Yates (2000), Billie Holiday (1959), Jim Morrison (1971), Lenny Bruce (1966), Peter Farndon (1983), Kurt Cobain (1994), Dee Dee Ramone (2002), Sid Vicious (1979), Corey Monteith (2013), Chris Kelly (2013), Michael Carl Baze (2011), Derek Boogaard (2011), Erica Blasberg (2010), Andy Irons (2010), Edward Fatu “Umaga” (2009), Billy Mays (2009), Christopher Bowman (2008), Scott Charles (“Bam Bam”) Bigelow (2007), Chris Mainwaring (2007), Ike Turner (2008), Anthony Durante (2003), Howie Epstein (2003), Elisa Bridges (2002), John Entwistle (2002), Darrell Porter (2002), Peter Jackson (1997), David Waymer (1993), Paul Hayward (1992), Chet Baker (1988), David Croudip (1988), Len Bias (1986), Don Rogers (1986), David Kennedy (1984)

Aunt Hazel, birdie powder, Black, Black Eagle, Black Pearl, Black Stuff, Black Tar, Boy, Brown, Brown Crystal, Brown Rhine, Brown Sugar Junk, Brown Tape, Chiba or Chiva, China White, dog food, Dope White, Dr. Feelgood, Dragon, H, He, hong-yen, Junk, lemonade, Mexican Brown, Mexican Horse, Mexican Mud, Mexican mud, Mud, Number 4, Number 8, old Steve, pangonadalot, Sack, Skag, Skunk Number 3, Smac, Snow, Snowball Scat, Tar, White Boy, White Girl, White Horse, White Lady, White Nurse, White Stuff, witch hazel

Type of drug combination	Street name
Heroin and Marijuana	Atom Bomb, Canade, Woola, Woolie, Woo-Woo
Heroin and Cold Medicine	Cheese
Heroin and Ecstacy	Chocolate Chip Cookies, H Bomb
Heroin and Alprazolam	Bars
Heroin and LSD	Beast, LBJ
Heroin and Cocaine	Belushi, Boy-Girl, He-She, Dynamite, Goofball, H&C, Primo, Snowball, speedball
Heroin and Crack	Chocolate Rock, Dragon Rock, Moonrock
Heroin and Ritalin	Pineapple

Channel Swimmer, Chasing the Dragon, Daytime (being high), Dip and Dab, Do Up, Evening (coming off the high), Firing the Ack Ack Gun, Give Wings, Jolly Pop, Paper Boy

Ac for Robitussin AC, C-plain for Corex Plain, Captain Cody, Cody, Decaprin for Mercodol Decaprin, Deka for Deka Syrup, Drank, Endo for Endotussin, Lean, Lotpurple, Slow, Syrup, Tikoy for Trecodin, Tuss or tussio for Tussionex

Blue, Hillbilly Heroin, Kicker, OC, OX, Oxy, Oxycotton, Poor man’s heroin

Dreamer, Duramorph, Emma, M, Miss Emma, Monkey, Morph, Roxanol, White stuff

Box or Boxes, Bupe, Oranges, Saboxin, Sobos, Stop signs, Stops, Sub or plural Subs

CCC, DXM, Orange crush, Red devils, Robo, Robo-trippin, skittles, Triple C, Tussin

Apache, Cash., China girl, China white, Dance fever, Friend, Goodfella, Jackpot, Murder 8, Tango, TNT

Footballs , Hydros, Pain killer, Percs, Perks, Pinks, Vikes

Demmies, Mapergan, Pethidine

Amidone, Dollies, Dolls, Done, Jungle juice, Junk, Maria, Meth, Methadose, Metho, Pastora, Phizzies, Phy, Wafer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shakiba Hassanzadeh, MD[2], Kiran Singh, M.D. [3]

Opioid withdrawal occurs due to the discontinuation or reduction of opioid use in individuals with heavy and prolonged opioid use or may be precipitated by the administration of an opioid antagonist in an individual with prolonged opioid use or by the administration of an opioid partial agonist in an individual that is currently using a full opioid agonist. Symptoms of withdrawal from opiates include, but are not limited to, depression, anxiety, irritability, leg cramps, abdominal cramps, nausea, vomiting, diarrhea, insomnia, pain, tremor, rhinorrhea, sweating, and cravings for the drug itself. Depending on the opioid‘s half-life, the symptoms of opioid withdrawal usually resolve within 5 to 14 days, however, many patients require appropriate treatment. The DSM-V diagnostic criteria is used for the diagnosis of opioid withdrawal. The medications for treatment include methadone, clonidine, buprenorphine, and adjunctive drugs.

• Opium and its derivatives have been used as medical therapies since 5,000 years ago.^[1]
• In the United States, in the early 20th century, opiates were over-the-counter drugs and were commonly used in medical therapy of various disorders.^[1]
• In the early 1900s, the federal restrictions on opioid access caused suffering and death since there were no effective treatments for the opioid withdrawal symptoms that happened with sudden discontinuation of opioids.^[1]

The onset and duration of opioid withdrawal depends on the half-life of the consumed opioid:^{[2][1][3][4][5]}

Half-life of Opioids	Onset of Withdrawal Symptoms	Duration of the syndrome
Short half-life Heroin at 3–5 h	Within 12 h of last use	Heroin withdrawal lasts 4–5 days
Long half-life Methadone up to 96 h	1–3 days after last use	Methadone withdrawal lasts 7–14 days Some last for several weeks

Chronic opioid use leads to changes in different organs and these may be the underlying pathophysiology of opioid withdrawal symptoms, such as:^[6][1]

• Gastrointestinal (GI) tract:
  • Mu opioid receptors:
    • Diarrhea, nausea and vomiting
• Brain:
  • Mesolimbic reward circuits (the ventral tegmental area and its projections to nucleus accumbens, prefrontal cortex and amygdala):
    • Opioid craving, compulsive use and depression
  • Ascending reticular activating system (in the brainstem, thalamus, and hypothalamus):
    • Insomnia
  • Different brain pathways (the locus coeruleus (LC) in the brainstem and its projections including those to the reticular activating system):
    • Physical dependence symptoms

Locus ceruleus(LC):^[6]

• Has norepinephrine (NE) neurons
• Input to several areas of the brain (prefrontal cortex, hippocampus and amygdala)
• Regulates attention, vigilance and autonomic nervous system

Acute opioid effects:

• Drowsiness, hypotension, reduced respiration and muscle tone
• Binding of an opioid to mu-opioid receptors on the neurons in LC causes:
  • Inhibition of the enzymes in the cAMP pathway
  • Decreased firing rate of LC neurons
  • Decreased NE release

Chronic opioid use:

Opioid tolerance occurs with the adaption of LC neurons to opioid inhibition by increasing enzyme activity which leads to:

• Upregulation of the cAMP pathway and production of normal cAMP levels:
  • Return to normal levels of LC firing rate and NE release

Abrupt discontinuation of opioids after opioid tolerance:

Sudden discontinuation of opioids in chronic opioid users that have opioid tolerance causes the following until re-adaptation to the absence of opioids occurs in LC neurons:^[7][8] 

• Hyperactivation of LC
• Increased production of cAMP
• Excessive release of NE

Noradrenergic hyperactivity is the main cause of acute opioid withdrawal symptoms.

Opioid withdrawal symptoms may occur with:^[9]

• Discontinuation or reduction of opioid use in individuals with heavy and prolonged opioid use.
• Precipitation by administrating of an opioid antagonist (such as naloxone or naltrexone) to an individual with prolonged opioid use.
• Precipitation by administrating of an opioid partial agonist (such as buprenorphine) to an individual that is currently using a full opioid agonist.

Opioid withdrawal must be differentiated from:^[10]

• Sedative-hypnotic withdrawal
• Hallucinogen intoxication
• Stimulant intoxication
• Opioid-induced depressive disorder

Disease	Prominent clinical features	Investigations
Hyperthyroidism	The main symptoms include: Palpitations Insomnia Anxiety Weight loss Heat intolerance Diarrhea Depending on the underlying diagnosis, the patient might have exophthalmos or goiter	The patient usually has elevated T3 and T4 TSH might be increased or decreased depending on the underlying cause Thyroid-stimulating antibodies (TSI) might be increased in cases of Graves’ disease
Essential hypertension	Most patients with hypertension are asymptomatic at the time of diagnosis. Common symptoms are listed below: Headache Blurry vision Dyspnea Epistaxis Tinnitus Fatigue Drowsiness	JNC 7 recommends the following routine laboratory tests before initiation of therapy for hypertension: A 12-Lead electrocardiogram (ECG) Urinalysis, including urinary albumin excretion or albumin/creatinine ratio Blood glucose Blood hematocrit Serum electrolytes, especially potassium Serum calcium Lipid profile: Total cholesterol, LDL, HDL, triglycerides Creatinine or estimated GFR
Generalized anxiety disorder	According to DSM V, the following criteria should be present to fit the diagnosis of generalized anxiety disorder: The presence of a sense of apprehension or fear toward certain activities for most of the days for at least 6 months Difficulty to control the apprehension Associated restlessness, fatigue, irritability, difficult concentration, muscle tension or, sleep disturbance (only one of these manifestations) The anxiety or the physical manifestations must affect the social and the daily life of the patient Exclusion of another medical condition or the effect of another administered substance Exclusion of another mental disorder causing the symptoms	–
Menopause	The perimenopausal symptoms are caused by an overall drop, as well as dramatic but erratic fluctuations, in the levels of estrogens, progestin, and testosterone. Some of these symptoms such as formication, etc. may be associated with the hormone withdrawal process. Vasomotor instability in the form of hot flashes, including night sweats and sleep disturbances Urogenital atrophy causing itching, dryness, bleeding, watery discharge, urinary frequency, urinary urgency and urinary incontinence Skeletal symptoms in the form of osteoporosis (gradually developing over time), arthralgia, myalgia, and back pain Psychological manifestations such as mood disturbance, irritability, fatigue, memory loss, and depression Sexual disorders: decreased libido, vaginal dryness, problems reaching orgasm, and dyspareunia	B-HCG should always be done first to rule out pregnancy especially in women under the age of 45 years FSH can be measured but it can be falsely normal or low TSH, T3, and T4 to rule out thyroid abnormalities Prolactin can be measured to rule out prolactinoma as a cause of menopause
Opioid withdrawal disorder	According to DSM V, the following criteria should be present to fit the diagnosis of opioid withdrawal: Cessation of (or reduction in) opioid use that has been heavy and prolonged (i.e., several weeks or longer) or administration of an opioid antagonist after a period of opioid use. Development of three or more of the following criteria minutes to days after cessation of drug use: dysphoric mood, nausea or vomiting, muscle aches, Lacrimation or rhinorrhea, pupillary dilation, piloerection, or sweating, diarrhea, yawning, fever, and insomnia. The signs or symptoms mentioned above must cause impairment of the daily functioning of the patient. The signs or symptoms mentioned above must not be attributed to other medical or mental disorders.	Urine drug screen to rule out any other associated drug abuse Routine blood work such as electrolytes and hemoglobin to rule out any associated disease explaining the symptoms
Pheochromocytoma	The hallmark symptoms of pheochromocytoma are those of sympathetic nervous system hyperactivity, symptoms usually subside in less than one hour and they may include: Palpitations especially in epinephrine-producing tumors. Anxiety often resembling that of a panic attack Sweating Headaches occur in 90% of patients. Paroxysmal attacks of hypertension but some patients have normal blood pressure. It may be asymptomatic and discovered by incidence screening, especially in MEN patients. Please note that not all patients with pheochromocytoma experience all of the classical symptoms.	Diagnostic lab findings associated with pheochromocytoma include: Elevated plasma and urinary catecholamines and metanephrines Elevated urinary vanillyl mandelic acid

• The prevalence of opioid withdrawal is 6,000 per 100,000 (60%) of the population that have used heroin one or more time in the prior 12 months.^[10]
• In the USA, the amount of opioids prescribed has increased from 43.8 million prescriptions in 2000 to 89.2 million in 2010.^[11]
• About 4% of adults in the USA regularly use opioids for pain.^[12]

Opioid withdrawal may be caused by discontinuation of repeated use of an opioid in any setting such as:^[10]

• Medical therapy of pain
• Opioid agonist therapy for opioid use disorder
• Recreational use
• Self-treating the symptoms of mental disorders

• Depending on the opioid‘s half-life, the symptoms of opioid withdrawal usually resolve within 5 to 14 days.
• However, many patients require appropriate treatment since the symptoms and distress is severe in the first days after the cessation of opioid use.^[13][14]
• Potential complications of discontinuing opioid use may include:^[15]
  • Emergence of pain
  • Exacerbation of a preexisting pain
  • Requirement of higher doses of opioid to manage pain

“

A. Presence of either of the following; 1. Cessation of (or reduction in) opioid use that has been heavy and prolonged (i.e., several weeks or longer). 2. Administration of an opioid antagonist after a period of opioid use. AND B. Three (or more) of the following developing within minutes to several days after Criterion A: 1. Dysphoric mood 2. Nausea or vomiting 3. Muscle aches 4. Lacrimation or rhinorrhea 5. Pupillary dilation, piloerection, or sweating 6. Diarrhea 7. Yawning 8. Fever 9.Insomnia AND C. The signs or symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. AND D. The signs or symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication or withdrawal from another substance.

”

The most common symptoms of opioid withdrawal include :^[16][17]

• Anxiety
• Restlessness
• Irritability
• Insomnia
• Hot flashes
• Chills
• Sweating
• Pupillary dilatation
• Heart pounding
• Lacrimation
• Rhinorrhea
• Yawning
• Gooseflesh
• Nausea, vomiting
• Abdominal cramps
• Diarrhea
• Aches, pain
• Muscle spasms, twitching
• Tremor

Common physical examination findings of opioid withdrawal include:^[16][17][1]

• Anxiety
• Restlessness
• Irritability
• Hypertension
• Tachycardia
• Mydriasis
• Piloerection (such as goose bumps)
• Lacrimation
• Rhinorrhea
• Yawning
• Nausea, vomiting
• Diarrhea
• Sweating
• Muscle spasms, twitching
• Tremor

Patients with opioid use disorder (particularly intravenous heroin dependence) may be tested for complications:^[18]

• Laboratory tests
• Tuberculosis
• HIV/AIDS
• Viral hepatitis (especially B and C)
• Other sexually transmitted diseases
• Opportunistic infections

There are no x-ray findings associated with opioid withdrawal.

There are no echocardiography/ultrasound findings associated with opioid withdrawal.

There are no CT scan findings associated with opioid withdrawal.

There are no MRI findings associated with opioid withdrawal.

There are no other imaging findings associated with opioid withdrawal.

Several scales are used in opioid withdrawal syndrome including:^[19]

• Short Opioid Withdrawal Scale (SOWS)^[20][21]
• Objective Opiate Withdrawal Scale (OOWS)^[21]
• Opiate Craving Scale (OCS)
• Opiate Withdrawal Scale (OWS)

Medications used in opioid withdrawal include:^[18]

• Methadone
  • Methadone is a long-acting agonist at the μ-opioid receptor
  • Dose:
    • The initial dose is determined by estimating the amount of opioid use and the patient’s response.
    • Methadone may be administered once daily, and tapered over 3 to 5 days (in 5 to 10mg daily reductions)
  • Methadone is the most commonly used medication, but patients require adjunctive drugs for nausea, vomiting, diarrhea, and stomach cramps
• Clonidine
  • Clonidine is an α-adrenergic agonist
  • Administered 0.1mg orally
  • A dose of 0.2mg might be used initially in patients:
    • With severe signs of opioid withdrawal
    • Weighing more than 200 pounds
  • Treatment with clonidine requires adjunctive drugs for insomnia, myalgia, bone pain, and headache.
• Buprenorphine
  • Buprenorphine is a partial μ-opioid agonist

• Lofexidine  
  • Has been approved in the United Kingdom for treatment of opioid withdrawal since 1992^[1] 
  • Lofexidine is an α-adrenergic agonist^[19]

Surgical intervention is not recommended for the management of opioid withdrawal.

• Refraining from sudden and abrupt discontinuation of opioid use in individuals with opioid dependence.
• Opioid replacement therapy (replace short-acting opioids with long-acting opioids). 
• Opioid tapering (gradual reduction in opioid dose).^[15]
• Early diagnosis and treatment of opioid use dependence.
• Long-term treatment of opioid use dependence.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Morphine and other poppy-based medicines have been identified by the World Health Organisation 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.^[1]. 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 Organisation is now working with different countries’ national administrations to train healthworkers and to develop national regulations regarding drug prescription in order to facilitate a greater prescription of poppy-based medicines.^[2]

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.

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