Pharmacodynamics +<unk>  at opioid receptors Compound Affinities () Ratio Ref<unk> R:DOR:KOR<unk>  1.8 nM 90 nM 317 nM 1:50:176 (−)-Morphine 1.24 nM 145 nM 23.4 nM 1:117:19 (+)-Morphine >10 μM >100 μM >300 μM + Equianalgesic doses Compound Route Dose Codeine 200 mg Hydrocodone 20–30 mg Hydromorphone 7.5 mg Hydromorphone 1.5 mg<unk>  30 mg<unk>  10 mg Oxycodone 20 mg Oxycodone 10 mg Oxymorphone 10 mg Oxymorphone 1 mg<unk>  is the prototypical opioid and is the standard against which other opioids are tested. It interacts predominantly with the μ–δ-opioid <unk> -Delta) receptor heteromer. The μ-binding sites are discretely distributed in the human brain, with high densities in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve.<unk>  is a phenanthrene opioid receptor agonist – its main effect is binding to and activating the μ-opioid receptor <unk> R) in the central nervous system. Its intrinsic activity at the<unk> R is heavily dependent on the assay and tissue being tested; in some situations it is a full agonist while in others it can be a partial agonist or even antagonist. In clinical settings,<unk>  exerts its principal pharmacological effect on the central nervous system and gastrointestinal tract. Its primary actions of therapeutic value are analgesia and sedation. Activation of the<unk> R is associated with analgesia, sedation, euphoria, physical dependence, and respiratory depression.<unk>  is also a κ-opioid receptor (KOR) and δ-opioid receptor (DOR) agonist. Activation of the KOR is associated with spinal analgesia, miosis (pinpoint pupils), and psychotomimetic effects. The DOR is thought to play a role in analgesia. Although<unk>  does not bind to the σ receptor, it has been shown that σ receptor agonists, such as (+)-pentazocine, inhibit<unk>  analgesia, and σ receptor antagonists enhance<unk>  analgesia, suggesting downstream involvement of the σ receptor in the actions of<unk> . The effects of<unk>  can be countered with opioid receptor antagonists such as naloxone and naltrexone; the development of tolerance to<unk>  may be inhibited by NMDA receptor antagonists such as ketamine or dextromethorphan. The rotation of<unk>  with chemically dissimilar opioids in the long-term treatment of pain will slow down the growth of tolerance in the longer run, particularly agents known to have significantly incomplete cross-tolerance with<unk>  such as levorphanol, ketobemidone, piritramide, and methadone and its derivatives; all of these drugs also have NMDA antagonist properties. It is believed that the strong opioid with the<unk> st incomplete cross-tolerance with<unk>  is either methadone or dextromoramide.<unk>  Hydrochloride Ampoule for Veterinary Use Gene expression Studies have shown that<unk>  can alter the expression of a number of genes. A single injection of<unk>  has been shown to alter the expression of two major groups of genes, for proteins involved in mitochondrial respiration and for cytoskeleton-related proteins. Effects on the immune system<unk>  has long been known to act on receptors expressed on cells of the central nervous system resulting in pain relief and analgesia. In the 1970s and '80s, evidence suggesting that opioid drug addicts show increased risk of infection (such as increased pneumonia, tuberculosis, and HIV/AIDS) led scientists to believe that<unk>  may also affect the immune system. This possibility increased interest in the effect of chronic<unk>  use on the immune system. The first step of determining that<unk>  may affect the immune system was to establish that the opiate receptors known to be expressed on cells of the central nervous system are also expressed on cells of the immune system. One study successfully showed that dendritic cells, part of the innate immune system, display opiate receptors. Dendritic cells are responsible for producing cytokines, which are the tools for communication in the immune system. This same study showed that dendritic cells chronically treated with<unk>  during their differentiation produce<unk> re interleukin-12 (IL-12), a cytokine responsible for promoting the proliferation, growth, and differentiation of T-cells (another cell of the adaptive immune system) and less interleukin-10 (IL-10), a cytokine responsible for promoting a B-cell immune response (B cells produce antibodies to fight off infection). This regulation of cytokines appear to occur via the p38 MAPKs (mitogen-activated protein kinase)-dependent pathway. Usually, the p38 within the dendritic cell expresses TLR 4 (toll-like receptor 4), which is activated through the ligand LPS (lipopolysaccharide). This causes the p38 MAPK to be phosphorylated. This phosphorylation activates the p38 MAPK to begin producing IL-10 and IL-12. When the dendritic cells are chronically exposed to<unk>  during their differentiation process then treated with LPS, the production of cytokines is different. Once treated with<unk> , the p38 MAPK does not produce IL-10, instead favoring production of IL-12. The exact mechanism through which the production of one cytokine is increased in favor over another is not known.<unk> st likely, the<unk>  causes increased phosphorylation of the p38 MAPK. Transcriptional level interactions between IL-10 and IL-12 may further increase the production of IL-12 once IL-10 is not being produced. This increased production of IL-12 causes increased T-cell immune response. Further studies on the effects of<unk>  on the immune system have shown that<unk>  influences the production of neutrophils and other cytokines. Since cytokines are produced as part of the immediate immunological response (inflammation), it has been suggested that they may also influence pain. In this way, cytokines may be a logical target for analgesic development. Recently, one study has used an animal<unk> del (hind-paw incision) to observe the effects of<unk>  administration on the acute immunological response. Following hind-paw incision, pain thresholds and cytokine production were measured. Normally, cytokine production in and around the wounded area increases in order to fight infection and control healing (and, possibly, to control pain), but pre-incisional<unk>  administration (0.1 mg/kg to 10.0 mg/kg) reduced the number of cytokines found around the wound in a dose-dependent manner. The authors suggest that<unk>  administration in the acute post-injury period may reduce resistance to infection and may impair the healing of the wound. Pharmacokinetics Absorption and metabolism<unk>  can be taken orally, sublingually, bucally, rectally, subcutaneously, intranasally, intravenously, intrathecally or epidurally and inhaled via a nebulizer. As a recreational drug, it is becoming<unk> re common to inhale ("Chasing the Dragon"), but, for medical purposes, intravenous (IV) injection is the<unk> st common method of administration.<unk>  is subject to extensive first-pass metabolism (a large proportion is broken down in the liver), so, if taken orally, only 40% to 50% of the dose reaches the central nervous system. Resultant plasma levels after subcutaneous (SC), intramuscular (IM), and IV injection are all comparable. After IM or SC injections,<unk>  plasma levels peak in approximately 20 min, and, after oral administration, levels peak in approximately 30 min.<unk>  is metabolised primarily in the liver and approximately 87% of a dose of<unk>  is excreted in the urine within 72 h of administration.<unk>  is metabolized primarily into<unk> -3-glucuronide (M3G) and<unk> -6-glucuronide (M6G) via glucuronidation by phase II metabolism enzyme UDP-glucuronosyl transferase-2B7 (UGT2B7). About 60% of<unk>  is converted to M3G, and 6% to 10% is converted to M6G. Not only does the metabolism occur in the liver but it may also take place in the brain and the kidneys. M3G does not undergo opioid receptor binding and has no analgesic effect. M6G binds to μ-receptors and is half as potent an analgesic as<unk>  in humans.<unk>  may also be metabolized into small amounts of normorphine, codeine, and hydromorphone. Metabolism rate is determined by gender, age, diet, genetic makeup, disease state (if any), and use of other medications. The elimination half-life of<unk>  is approximately 120 min, though there may be slight differences between men and women.<unk>  can be stored in fat, and, thus, can be detectable even after death.<unk>  can cross the blood–brain barrier, but, because of poor lipid solubility, protein binding, rapid conjugation with glucuronic acid and ionization, it does not cross easily. Heroin, which is derived from<unk> , crosses the blood–brain barrier<unk> re easily, making it<unk> re potent. Extended-release There are extended-release formulations of orally administered<unk>  whose effect last longer, which can be given once per day. Brand names for this formulation of<unk>  include Avinza, Kadian,<unk>  Contin and Dolcontin. For constant pain, the relieving effect of extended-release<unk>  given once (for Kadian) or twice (for<unk>  Contin) every 24 hours is roughly the same as<unk> ltiple administrations of immediate release (or "regular")<unk> . Extended-release<unk>  can be administered together with "rescue doses" of immediate-release<unk>  as needed in case of breakthrough pain, each generally consisting of 5% to 15% of the 24-hour extended-release dosage. Detection in body fluids<unk>  and its major metabolites,<unk> -3-glucuronide and<unk> -6-glucuronide, can be detected in blood, plasma, hair, and urine using an immunoassay. Chromatography can be used to test for each of these substances individually. Some testing procedures hydrolyze metabolic products into<unk>  before the immunoassay, which<unk> st be considered when comparing
Morphine
Codeine
Nalorphine
Methadone
Isomethadone
Normethadone
Butorphanol
Fentanyl