Safety

Studies 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, and that sedative dose increases were not associated with shortened survival (n=237). Another UK study showed that the respiratory rate was not changed by morphine given for breathlessness to patients with poor respiratory function (n=15). In Australia, no link was found between doses of opioids, benzodiazepines or haloperidol and survival. In Taiwan, a study showed that giving morphine to treat breathlessness on admission and in the last 48 hours did not affect survival. The survival of Japanese patients on high dose opioids and sedatives in the last 48 hours was the same as those not on such drugs. In U.S. patients whose ventilators were being withdrawn, opioids did not speed death, while benzodiazepines resulted in longer survival (n=75). Morphine given to elderly patients in Switzerland for breathlessness showed no effect on respiratory function (n=9, randomised controlled trial). 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. Even when opioids are given intravenously, respiratory depression is not seen.

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

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

Tolerance

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. However, tolerance does not develop to constipation or miosis.

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

  • calcium channel blockers
  • intrathecal magnesium and zinc
  • NMDA antagonists, such as dextromethorphan or ketamine
  • cholecystokinin antagonists, such as proglumide
  • Newer agents such as the phosphodiesterase inhibitor ibudilast have also been researched for this application.

Magnesium and zinc deficiency speed up the development of tolerance to opioids and relative deficiency of these minerals is quite common 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

Dependence is characterised 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, rhinorrea, depression, severe fatigue, vomiting and pain. Slowly reducing the intake of opioids over days and weeks will reduce or eliminate the withdrawal symptoms. The speed and severity of withdrawal depends on the half-life of the opioid; heroin and morphine withdrawal occur more quickly and are more severe than methadone withdrawal, 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, such as clonidine, antidepressants and benzodiazepines, but with a low efficacy.

Addiction

Addiction is the process whereby physical and/or psychological dependence 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.

Misuse

Drug misuse is the use of drugs for reasons other than what the drug was prescribed for. Opioids are primarily misused due to their ability to produce euphoria.

Examples

Endogenous opioids

Opioid-peptides that are produced in the body include:

  • Endorphins
  • Enkephalins
  • Dynorphins
  • Endomorphins

ß-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. ß-endorphin has many effects, including on sexual behavior and appetite. ß-endorphin is also secreted into the circulation from pituitary corticotropes and melanotropes. a-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 d-opioid receptors. leu-enkephalin, also a product of the proenkephalin gene, acts through d-opioid receptors.Dynorphin acts through ?-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.

Opium alkaloids

Phenanthrenes naturally occurring in opium:

  • Codeine
  • Morphine
  • Thebaine
  • Oripavine

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

Semisynthetic derivatives

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

Synthetic opioids

Anilidopiperidines

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

Phenylpiperidines

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

Diphenylpropylamine derivatives

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

Benzomorphan derivatives

  • Dezocine - agonist/antagonist
  • Pentazocine - agonist/antagonist
  • Phenazocine

Oripavine derivatives

  • Buprenorphine - partial agonist
  • Dihydroetorphine
  • Etorphine

Morphinan derivatives

  • Butorphanol - agonist/antagonist
  • Nalbuphine - agonist/antagonist
  • Levorphanol
  • Levomethorphan

Others

  • Lefetamine
  • Meptazinol
  • Tilidine
  • Tramadol
  • Tapentadol

Opioid antagonists

  • Nalmefene
  • Naloxone
  • Naltrexone
Source: Wikipedia

See also

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