What are opioid analgesics?HistoryMorphineMechanism of opioidsSide effects

Adverse reactionsAddiction, overdose and withdrawal symptomsOpiophobiaOpioids of abuse

HeroinFentanyl

Future of opioids

Analgesics, or pain killers, that bind to opioid receptors which are found principally in the:

CNS Gastrointestinal tract

There are a number of broad classes of opioids: Natural opiates

Alkaloids contained in the resin of the opium poppy including morphine, codeine and thebaine

Semi-synthetic Opiates Created from the natural opioids such as hydromorphone,

oxycodone and diacetylmorphine (heroin) Fully synthetic opioids

Fentanyl, methadone and tramadol Endogenous opioid peptides

Proudced naturally in the body, such as endorphins, enkephalins, dynorphins and endomorphins

Opioids have been the mainstay of pain treatment for thousand of years, and they remain so todayThe search for a safe, orally active, and non-addictive analgesic based on the opiate structure is one of the oldest fields in medicinal chemistryThe opiates are perhaps the oldest drugs known to humanity

The first undisputed reference to opium is found in the writings of Theophrastus in the third century B.C.The use of opium was recorded in China over 2000 years ago, and was known in Mesopotamia before that

Its use in medicine is quoted in a twelfth-century prescription:

Take opium ,mandragora, and henbane in equal parts and mix with water. When you want to saw or cut a man, dip a rag in this and put it to his nostrils. He will sleep so deep that you may do what you wish.

Opium contains a complex mixture of 20 alkaloids, principle one being morphine› Responsible for analgesic activity

Because of morphine’s poor oral bioavailability, it was little used in medicine until the hypodermic syringe was invented in 1853

Morphine was used during the American Civil War and the Franco-Prussian war.› Due to poor understanding about:

Safe dose levels Effects of long-term use And increased risks of addiction, tolerance and

respiratory depression› Many casualties were either killed by overdoses or

became addicted to the drug

3-D Structure of Morphine

In general, opioids act upon mu-, delta-, and kappa-receptors on CNS neurons producing:

Analgesia via decreased neuronal transmitter release and decreased nociceptive impulse propagation

Appears to work by elevating the pain threshold, thus decreasing the brain’s awareness of pain

Receptor type

Location Effects

μ Brain, spinal cord

Analgesia, respiratory depression, euphoria, addiction, ALL pain messages blocked

κ Brain, spinal cord

Analgesia, sedation, all non-thermal pain messages blocked

δ Brain Analgesia, antidepression, dependence

As with many drug therapeutics that cross the BBB and take effect in the CNS, the mechanism of opioid derivatives is not completely understoodFor this reason, there is still biochemical/pharmacological studies being conducted to try to understand how these drugs workA new study from last year was able to biotinylate various opioid derivatives to aid in these types of studies which are still very common

Biotinylation-process of covalently attaching a biotin (vitamin H or B7) tag to a molecule or surface

Dangerous side effects are those of tolerance and dependence, allied with the effects morphine can have on breathing› Most common cause of death from

morphine overdose is suffocation› These side effects in one drug are

particularly dangerous and lead to severe withdrawal symptoms when the drug is no longer taken

AnorexiaWeight lossPupil dilationChillsExcessive sweatingAbdominal crampsMuscle spasmsHyperirritabilityLacrimationTremorIncreased heart rateIncreased blood pressure

A study was done in W. Virginia to evaluate persons dying of unintentional pharmaceutical overdose, the types of drugs involved and role of drug abuse in the deathsOpioid analgesics were taken by 93.2% (275/295) of all people who died of pharmaceutical overdoses in W. Virginia in 2006Only 44.4% (122/275) of those people had ever been prescribed these drugsThe majority of overdose deaths in West Virginia in 2006 were associated with nonmedical use and diversion of pharmaceuticals, primarily opioid analgesics

The fear of prescribing opioid pain medications is known as "opiophobia”

Goodman and Gillman’s Pharmacological Basis of Therapeutics insists that although physical dependence and tolerance may develop, this should not in any way prevent physicians from fulfilling their primary obligation to ease the patient’s discomfort

No patient should ever wish for death because of a physician’s reluctance to use adequate amounts of effective opioids

Physical dependence is not equivalent to addiction

First synthesized in 1874 by an English chemist but only became popular more than 20 years later

From 1898 through 1910, under the name heroin, diacetylmorphine was marketed as a non-addictive morphine substitute and cough suppressant

A heroin overdose is usually treated with an opioid antagonist, such as naloxone (Narcan) which has high affinity for opioid receptors but does not activate themMany fatalities reported as overdoses are probably caused by interactions with other depressant drugs like alcohol or benzodiazepinesIt has been speculated that an unknown portion of heroin related deaths are the result of an overdose or allergic reaction to quinine, which may sometimes be used as a cutting agentA final factor contributing to overdoses is place conditioning. Heroin use is a highly ritualized behavior

Morphine Fentanyl

1959-Fentanyl first synthesized by Paul Janssen under Janssen Pharmaceutica

1960s-Introduced as intravenous anesthetic (Sublimaze)

1990’s-same company produced Duragesic patch

Next came Actiq, flavored lollipop of fentanyl citrate

Present-Effervescent tab for buccal absorption and buccal spray device

The pharmaceutical industry has developed several analogues of fentanyl:

Alfentanil (Alfenta), an ultra-short acting (5-10 minutes) analgesic

Sufentanil (trade name Sufenta), a potent analgesic (5 to 10 times more potent than fentanyl) for use in heart surgery

Remifentanil (trade name Ultiva), currently the shortest acting opioid, has the benefit of rapid offset, even after prolonged infusions

Carfentanil (Wildnil) is an analogue of fentanyl with an analgesic potency 10,000 times that of morphine and is used in veterinary practice to immobilize certain large animals such as elephants

Fentanyl is normally sold on the black market in the form of transdermal fentanyl patches such as Duragesic, diverted from legitimate medical supplies

the patches may be cut up and eaten, or the gel from inside the patch smoked

Another dosage form of fentanyl that has appeared on the streets is fentanyl lollipops Actiq, which are sold under the street name of "percopop”

They are sold for anywhere from $15-$40 per unitSome heroin dealers mix fentanyl powder with larger amounts of heroin in order to increase potency or compensate for low-quality heroin, and to increase the volume of their product

As of December 2006, a mix of fentanyl and either cocaine or heroin have caused an outbreak in overdose deaths in the United StatesThe mixture of fentanyl and heroin is known as "magic" or "the bomb", among other names, on the street

Generic Name Brand Name

buprenorphine Buprenexbutorphanol Stadolcodeine Tylenol with codeinefentanyl Duragesichydrocodone Vicodinhydromorphone Dilaudidmethadone Dolophinemorphine Astramorphoxycodone OxyContinporpoxyphene Darvon

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