Overdose

A morphine overdose occurs by intentionally or accidentally taking too much of it. A large overdose can cause asphyxia and death by respiratory depression if the person does not get medical attention or an antidote (Naloxone) immediately.

Treatments include administration of activated charcoal, intravenous fluids, laxatives and naloxone. The latter completely reverses morphine's effects, but precipitates immediate onset of withdrawal in opiate-addicted subjects. Multiple doses of it may be needed.

The minimum lethal dose is 200 mg but in case of hypersensitivity 60 mg can bring sudden death. In case of drug addiction, 2-3 g/day can be tolerated. See L. Macchiarelli P. Arbarello G. Cave Bondi N.M. Di Luca T.Feola Medicina Legale (compendio) II edition ; Minerva Medica Publications, Italy, Turin 2002Effects on other systems and processes

It has been said by various sources for at least 200 years that under ideal circumstances, use of opium and its derivatives and synthetic analogues may promote longevity and slow or switch off the aging process. In practice, any such effect would have to compete with whatever comorbid conditions the medical patient has and the health problems the unsupervised user may have as the result of the illegality, cutting agents, purity, and other properties of the drugs he or she actually ingest and otherwise. However, the fact that opioids slow metabolism, lower blood pressure, moderate blood sugar levels, and have the above-listed acute and chronic effects on the endocrine system, blood, heart, and lungs (all other things being equal) may be a reason for this supposition, as examples of opioid-use careers from 50 to 100 years in length are uncommon but certainly in existence, even in the 19th century, when the life expectancy was lower. Some users of opioids both under medical care and unsupervised may look younger after several years of use on account of hormonal effects and skin changes related to opioid effects.

In the late 1990s, research into the neurological and other systemic effects of what was initially presumed to be somewhat average lower blood oxygen concentrations in chronic users of opioids which create respiratory depression led to inconclusive results.

The theory that high dose protracted opioid use may, by itself, harm the liver or kidneys does not appear to have a basis in empirically determined medical fact, however, the fluid-balance problems attendant to opioid withdrawal could eventually lead to a higher incidence of kidney stones if not treated properly, and the paracetamol content of many proprietary medications containing weak and mid-range opioids like hydrocodone can certainly be injurious to some bodily systems, as can massive and/or chronic overdoses of aspirin, salicylates, ibuprofen, and other NSAIDs.

Central hypogonadism is seen in some long-term opioid users. The effect is more commonly seen with methadone than it is with morphine or codeine. The effects of this and other changes to the body make morphine and opium a crude form of female birth control, and lower sperm counts are seen in male subjects, as well as erectile dysfunction and decrease in libido in such cases of central hypogonadism secondary to opioid use.

Contraindications

The following conditions are relative contraindications for morphine:

  • acute respiratory depression
  • renal failure (due to accumulation of the metabolites morphine-3-glucuronide and morphine-6-glucuronide)
  • chemical toxicity (potentially lethal in low tolerance subjects)
  • raised intracranial pressure, including head injury (risk of worsening respiratory depression)
  • Biliary colic.

Although it has previously been thought that morphine was contraindicated in acute pancreatitis, a review of the literature shows no evidence for this.

Pharmacology

Endogenous opioids include endorphins, enkephalins, dynorphins, and even morphine itself. Morphine appears to mimic endorphins. Endogenous endorphins are responsible for analgesia (reducing pain), causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or excitement.

Morphine is the prototype narcotic drug and is the standard against which all other opioids are tested. It interacts predominantly with the µ-opioid receptor. These 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.Morphine is a phenanthrene opioid receptor agonist – its main effect is binding to and activating the µ-opioid receptors in the central nervous system. In clinical settings, morphine 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 µ-opioid receptors is associated with analgesia, sedation, euphoria, physical dependence, and respiratory depression. Morphine is a rapid-acting narcotic, and it is known to bind very strongly to the µ-opioid receptors, and for this reason, it often has a higher incidence of euphoria/dysphoria, respiratory depression, sedation, pruritus, tolerance, and physical and psychological dependence when compared to other opioids at equianalgesic doses. Morphine is also a ?-opioid and d-opioid receptor agonist, ?-opioid's action is associated with spinal analgesia, miosis (pinpoint pupils) and psychotomimetic effects. d-opioid is thought to play a role in analgesia. Although morphine does not bind to the s-receptor, it has been shown that s-agonists, such as (+)-pentazocine, antagonize morphine analgesia, and s-antagonists enhance morphine analgesia, suggesting some interaction between morphine and the s-opioid receptor.The effects of morphine can be countered with opioid antagonists such as naloxone and naltrexone; the development of tolerance to morphine may be inhibited by NMDA antagonists such as ketamine or dextromethorphan. The rotation of morphine 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 morphine 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 most incomplete cross-tolerance with morphine is either methadone or dextromoramide.

Gene expression

Studies have shown that morphine can alter the expression of a number of genes. A single injection of morphine 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

Morphine 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 opiate drug addicts show increased risk of infection (such as increased pneumonia, tuberculosis, and HIV) led scientists to believe that morphine may also affect the immune system. This possibility increased interest in the effect of chronic morphine use on the immune system.

The first step of determining that morphine 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 morphine during their differentiation produce more 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 cell is chronically exposed to morphine during their differentiation process then treated with LPS, the production of cytokines is different. Once treated with morphine, 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. Most likely, the morphine 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. Future research may target the exact mechanism that increases the production of IL-12 in morphine treated dendritic cells. This increased production of IL-12 causes increased T-cell immune response. This response is due to the ability of IL-12 to cause T helper cells to differentiate into the Th1 cell, causing a T cell immune response.

Further studies on the effects of morphine on the immune system have shown that morphine 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 model (hind-paw incision) to observe the effects of morphine 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 morphine administration (0.1-10.0 mg/kg) reduced the number of cytokines found around the wound in a dose-dependent manner. The authors suggest that morphine administration in the acute post-injury period may reduce resistance to infection and may impair the healing of the wound.

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