Opioids
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 four broad classes of opioids:
- endogenous opioid peptides (opioids produced naturally in the body);
- opium alkaloids, such as morphine (the first alkaloid isolated from opium) and codeine;
- semi-synthetic opioids, such as Heroin and oxycodone; and
- fully synthetic opioids, such as pethidine and methadone.
Endogenous opioids are opioid-peptides produced in the body. Endorphins act through mu-opioid receptors, and is more potent than other endogenous opioids at these receptors. Beta-endorphin is expressed in POMC cells in the arcuate nucleus and in a small population of neurons in the brainstem, and acts through mu-opioid receptors. Beta-endorphin has many effects, including on sexual behavior and appetite.Beta-endorphin is also secreted into the circulation from pituitary corticotropes and melanotropes. Alpha-neoendorphin is also expressed in POMC cells in the arcuate nucleus. Dynorphins acts through kapa-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. Met-enkephalin is widely distributed in the CNS. It is a product of the proenkephalin gene, and acts through mu- and sigma-opioid receptors. Leu-enkephalin , also a product of the proenkephalin gene, acts through sigma-opioid receptors.
Opium alkaloids chemically are phenanthrenes naturally occurring in opium:
- Morphine
- Codeine
- Thebaine
Preparations of mixed opium alkaloids, including papaveretum, are still occasionally used.
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.
Semisynthetic derivatives are:
- Diacetylmorphine (Heroin)
- Oxycodone
- Hydrocodone
- Dihydrocodeine
- Hydromorphone
- Oxymorphone
- Nicomorphine
Synthetic opioids are:
Anilidopiperidines
- Fentanyl
- Alfentanil
- Sufentanil
- Remifentanil
- Ohmefentanyl
Phenylpiperidines
- Pethidine (meperidine)
- Ketobemidone
- MPPP
- Allylprodine
- Prodine
- PEPAP
Diphenylpropylamine derivatives
- Propoxyphene
- Dextropropoxyphene
- Dextromoramide
- Bezitramide
- Piritramide
- Methadone
- 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)
Benzomorphane derivatives
- Pentazocine
- Phenazocine
Oripavine derivatives
- Buprenorphine
- Etorphine
Morphinane derivatives
- Butorphanol
- Nalbufine
- Levorphanol
- Levomethorphan
Others
- Dezocine
- Lefetamine
- Tilidine
- Tramadol
Naloxone ad Naltrexone are opioid antagonists.
PHARMACOLOGY
Opioids bind to specific opioid receptors in the central nervous system and in other tissues. There are at least seventeen major classes of opioid receptors, although only four are generally spoken of: mu, kapa, theta and possibly sigma. In addition, there are two subtypes of mu receptor: mu-1 and mu-2.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 mu-1 receptor, respiratory depression and physical dependence (dependency) by the mu-2 receptor, and sedation and spinal analgesia by the kapa-receptor.
CLINICAL USES
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 4 hours (90mg/24 hours), ie. 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 experience in palliative care of longterm use of strong opioids which has shown that dependence is rare when the drug is being used for pain relief.
United States: The sole clinical indications for opioids in the US, according to Drug Facts and Comparisons, 2005, are:
- Analgesia and anesthesia;
- Cough (codeine and hydrocodone only);
- Diarrhea (opium only);
- Anxiety due to shortness of breath (oxymorphone only); and
- Detoxification (methadone and buprenorphine only).
SIGNS OF OPIOID USE
An individual who uses opioids typically experiences:
- drowsiness ("nodding off")
- mood changes
- a feeling of heaviness
- dry mouth
- itching
- slurred speech.
Individuals who use Heroin intravenously describe:
- an intense euphoria (or “rush")
- a floating feeling
- total indifference to pain.
Symptoms of intoxication usually last several hours. Severe intoxication from an Overdose of opioids is life-threatening because breathing may stop.
OPIOID ABUSE AND ADDICTION
In opioid addiction (not seen in patients taking opioids for pain relief), the speed and severity of withdrawal depends on the half-life of the opioid - Heroin withdrawal occurs more quickly and is 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. Withdrawal symptoms can be minimised by slowly tapering the dose over days or weeks, sometimes after switching to a long-acting opioid such as methadone. The symptoms of opioid withdrawal can also be treated with other medications, such as clonidine for sympathetic hyperactivity and a benzodiazepine for anxiety and insomnia.
Occasionally, people who are addicted to opioids on the street develop a painful condition which requires strong opioids. Carers are often very reluctant to give these patients analgesia, fearing it will make their addiction worse. Paradoxically, increasing experience of caring for such patients in palliative care has shown that they can be managed in the same way as any other patient with regular administration of opioids, plus extra doses for breakthrough medication. It seems that, because the social context is fundamentally different to the one when they were abusing their drugs, they do not run the risk of addiction. Indeed, if the cause of the pain settles, they can reduce their opioids without problem.
The Diagnostic and Statistical Manual-IV-TR specifies that three or more of the following symptoms must occur at any time during a 12-month period (and cause significant impairment or distress) in order to meet diagnostic criteria for opioid dependence:
1) Tolerance: The individual either has to use increasingly higher amounts of the drug over time in order to achieve the same drug effect or finds that the same amount of the drug has much less of an effect over time than before.
2)Withdrawal: The individual either experiences the characteristic abstinence syndrome (i.e., opioid-specific withdrawal) or the individual uses opioids or similaracting drugs in order to avoid or relieve withdrawal symptoms.
3)Loss of control: The individual either repeatedly uses more opioids than planned or uses the opioids over longer periods of time than planned.
4)Inability to stop using: The individual has either unsuccessfully attempted to cut down or stop using the opioids or has a persistent desire to stop using.
5)Time: The individual spends a lot of time obtaining opioids, getting money to buy opioids, using opioids, being under the influence of opioids, and recovering from the effects of opioids.
6)Interference with activities: The individual either gives up or reduces the amount of time involved in recreational activities, social activities, and/or occupational activities.
7)Harm to self: The individual continues to use opioids despite having either a physical or psychological problem (depression, for example) that is caused or made worse by the opioid use.
Recovering from opioid dependence is a long, difficult process. Typically, multiple treatment attempts are required. Relapsing, or returning to opioids, is not uncommon even after many years of abstinence. Brief periods of abstinence are common. Inpatient detoxification from opioids alone, without additional treatment, does not appear to have any effect on opioid use. However, other treatments have been shown to reduce opioid use, decrease illegal activity, decrease rates of HIV-infection, reduce rates of death, and increase rates of employment. Benefits are greatest for those who remain in treatment longer and participate in many different types of treatment (individual and group counseling in addition to methadone maintenance, for example).
SOURCES:
National Institute of Drug Abuse. “Drugs, Brains, and Behavior - The Science of Addiction”
National Institute of Drug Abuse. Reaserch Report Series
The Gale Encyclopedia of Mental Disorders ©2003 by Gale.
World Health Organization. Neuroscience of Psychoactive Substance use and Dependence ©WHO 2004
World Health Organization. Lexicon of alcohol and drug terms
