Opiates

Opiates

• naturally occurring, derived, and synthetic compounds with analgesic properties

• often referred to as “narcotic analgesics”

• term “narcotic” re: opiates can be confusing as it categorizes the opiates with dissimilar drugs

Naturally Occurring

• poppy named papaver somniferum is natural source of opium

• morphine, codeine, and thebaine found in opum

• opium is the sap from seedpods of opium poppy

  • morphine- 10%

  • codeine -0.75 to 2.6%

  • thebaine - <1%

How to get opium from plants?

• flowers can be white, pink, or red

• when petals have fallen, small shallow incisions are made with a special knife-like instrument in the seedpod

• these scratches made in seedpod of poppy exude a milky white juice oozes out (raw opium) , over a day this substance harden (oxidizes) becomes reddish brown, or dark brown, and is heavy like syrup; formed small gumlike balls that look like tar, taste bitter, and smell like new mown hay.

• the opium is produced for an average of 10 days after petal drops

Opiate derivates/Semi-synthetics

• heroin

• hydromorphon

• oxycodon

• oxymorphone

• hydrocodone

• caused by having slight changes to chemical composition

Heroin

• heroin derived by adding acetyl groups to morphine molecule

• 3X more potent than morphine

• more lipid soluble than morphine

• schedule I drug, but may be legally prescribed

Hydromorphone

• derived from morphine; more than 10X potent to morphine

Oxycodone

• derived from thebaine

Oxymorphone

• derived from morphine; 1.5 X more potent than morphine

Hydrocodone

• derived from codeine; less potent than morphine

• hydrocodone + acetaminophen = vicodin

• hydrocodone + ibuprofen = vicoprofen

• hydrocodone + acetylsalicylic acid = alor

Meperdine

commonly prescribed pain-killer, less potent than morphine

Methadone

used to treat chronic pain and opiate dependency; as potent as morphine in terms of analgesic effect, less potent than morphine in terms of euphoric effects

Morphine

• most abundant active constituents of opium and poppy straw

• was isolated from opium by german chemist Frederick Sertuner

• Heinrich Emanuel Merck (founder of German company Merck Pharmaceuticals) becan manufacturing and selling morphine commercially in 1827

• widely used medically for pain management and is sold under its generic name morphine sulfate as well as a variety of trade names

Fentanyl

• marketed as sublimaze in 1960’s to treat chronic pain such as that experienced with cancer; 30 to 50X more potent than heroin

• available as oral transmucosal lozenges (street slang term is “lollipops”), sublingual tablets, effervescent buccal tablets, nasal sprays, transdermal patches, intravenous injectables

Fentanyl vs Heroin

fentanyl is being being preferred over street use of heroin, reasons given by users include;

• it has a greater rush

• it is cheaper

• greater availability

• healthier; decreased risk of blood borne viruses, decreased skin abscesses

• smoking involves heating powder and inhaling

Opiate antagonists

useful in treating overdoses

• naloxone

• naltrexone

Naloxone

• bran name Narcan- can be given IV or IM

• competivite antagonist at my, kappa, and delta receptors

• when given, will reverse depressed breathing in a matter of minutes

• when given, it will quickly induce withdrawal symptoms in individuals using an opiate

Naltrexone

• effects last a bit longer than naloxone

• naltrexone differs from naloxone in that it has some mild agonist morphine like effects

Opioid Uses

• medical uses include

  • treatment of pain

  • treatment of diarrhea

  • treatment of cough

Opioid Use and History

Medical use dates back hundreds of years

• documented in Egyptian medical scrolls dating back to 1550 BC. opium is mentioned in Egyptian Medical Scrolls for treatment of a number of conditions- one specific reference refers to it as a remedy to prevent the excessive crying of children

• in second century AD, Galen recommended it for practically everything

• in 1520, a physician called Parcelsus introduced a medicinal drink combining opium, wine and an assortment of spices, which he called laudanum

Tincture of Opium

contained 10% powdered opium dissolved in alcohol

Laundanum

• had about 45-65% alcohol and about 65 mg of opium (typically morphine), in other formulations, there would be more opium sometimes 3X more

• by the 1800s, there were dozens of patented laudanum based medicines that went by a variety of names, all with very appealing names, advertising their positive properties such as Mrs. Winslow’s Soothing Syrup, Godfrey’s Cordial, a Pennysworth of Peace

• Paracelus like Galen recommended laudanum for practically ever known disease and it was taken for a variety of reasons- women in the 18th century, were prescribed for menstrual pain and melancholy, following in the footsteps of Egyptians, mothers would give it to their children to keep them quiet ot treat colic, some people took it for toothache- and unfortunately for at leas one individual in the 1800’s Thomas DeQuincy it led to an addition to opium

Recreational Uses and History of Opium

• recreational use dates back hundreds of years (at least)

  • 2nd century AD: Galen noted that opium cakes and candy sold everywhere on the street

  • 18th century: opium dens appear in China, and elsewhere (e.g., North America, Asia, France) with Chinese “Invention” of Opium Smoking

  • most opium dens supplied their clientale with specialized pipes and lamps- lamps needed to smoke the drug

  • lamp to heat it until it vaporizes and the pipe to condense and inhale the smoke

  • opium dens in China were frequented by all levels of society, and their opulence or simplicity reflected the financial means of the patrons

  • in urban areas of the Unites states, particularly on the West Coast, there were opium dens that mirrored the best to be found in China. For the working class, there were also many low-end dens these dens were more likely to admit non-Chinese smokers.

  • There are references, indication of opium use prior to the 2nd C, a ceramic opium pipe dating to the Bronze Age was found in Cyprus

  • Opium dens were frequented by all levels of society, and their opulence or simplicity reflected the financial means of the patrons

Opium History

• up until early to mid 1800’s, opium use was widely socially accepted and not perceived as a social or medical problem

• was not a controlled substance and was widely available for both medical and recreational use and despite large number of individuals being addicted

• one source indicates that 250,000 people in the US alone were addicted to some type of opiate

• Mid to late 1800s saw some governmental efforts in US and Britain to regulate use and selling of drug

• some historians see this as a prejudicial reaction to the Chinese and their opium dens vs coming out of a genuine concern about the negative consequences of opium use

Governmental Efforts for Opium

• one of the governmental efforts was a city law passed in 1875, San Francisco which outlawed opium dens and a newspaper at the same time quoted “many women and young girls, as well as young men of respectable family, were being induced to visit the dens, where they were ruined morally and otherwise”

• one drug historian noted, no mention was ever made of any moral ruin coming out of drinking at home

• the other governmental action was a parliamentary bill in Britain in 1868 which made pharmacists shops the only legal source of opiates

Canada Opium Act 1908

• prohibited the “Importation, manufacture, and sale of opium for other than medicinal purposes”

• although it prohibited the use of opium by smokers, the act was aimed at dealers vs users and was followed up by Bill 205, an act to prohibit the importation, manufacture, and sale of opium for other than medicinal purpose

Canada: Opium and Narcotic AAct 1911

• prohibited the improper use of opium and other drugs

• intended to make it more restrictive and effective

• Mackenzie King introduced Bill 97

• section 14 of the act provided that the Governor in Council had the power to order any alkaloid, by-product or drug preparation added to the schedule when its addition was deemed necessary in the public interest- a power which still exists today, the justification given for this was that if the use of a new drug were to become widespread it society it would be possible to add it

Methods of administration

• Orally; opium eating

• Parenterally: intramuscularly, subcutaneously (skin popping), intravenously (mainlining)

• Via inhalation

• Transdermally

Distribution of Opium

• high concentrations in lungs, liver, spleen

• readily passes through placental barrier

• in brain, concentrated in limbic system, basal ganglia, nucleus accumbens, ventral tegmental areas, preiaqueductal gray area (pain area), brain stem

• infants born to addicted mothers will exhibit withdrawal symptoms

Metabolization

• codeine and much of heroin inactive until metabolized

• metabolization is rapid

  • exception is some of the synthetic compounds (e.g., methadone, LAAM)

• heroin metabolized into morphine

• codeine metabolized into morphine and other metabolites

• Heroin half-life = 30 min

• fentanyl half-life = 1 to 2 hours

• methadone half-life = 10-25 hours

• LAAM (levo alpha acetyl methadol) half life= 36 to 48 hours

Pharmacological Actions

• mimic endorphins

• agonist action at six types of receptors: mu, kappa, delta, sigma, episolon and lambda

• decrease rate of neuronal firing via two mechanisms:

  • inhibiting Ca influx: this decreasing or stopping release of NE, DA, Ach in presynaptic neuron (does this via opiate receptors on pre-synaptic neuron)

  • enhance flow of K

• increase firing in some neurons by preventing inhibition of those neurons (inhibition prevented by depressing/inhibiting “inhibitory” synapses)

• strong attachment vs strong effect: some opiates have weak attachment but strong effect, others the opposite eg., morphine at mu receptors have weak attachment (easily dislodged) but strong effect

Mu receptors

distributed throughout limbic system

Delta receptors

distributed throughout limbic system, but their distribution does not overlap with mu receptors

Kappa receptors

found in nucleus accumbens, ventral tegmental area, the hypothalamus and thalamus

CNS Effects

• analgesic effects

• depress respiratory center

• suppress cough center

• depress vomiting center

• drowsiness

• decrease levels of sex hormones

Analgesic Effects

1. occur through action at Mu, Delta, and Kappa receptors at the spinal cord- block incoming info from pain

2. increase activity in periaqueductal gray area. activation of periaqueductal gray area (whose neurons project to the raphe nuclei) leads to a release of serotonin at interneurons at the spinal cord. The activation of the interneurons leads to a release of enkephalins, or dynorphins, which then bind to opiate receptors on axons carrying pain signals and inhibit release of substance P and by doing the latter, this inhibits the activation of neurons responsible for transmitting pain signals up.

3. Alter aversive emotion associated with pain: mediated by receptors in limbic system and frontal love

Vomiting center

• initial effects are excitatory with nausea and vomiting seen, which is why when people are given opiates for the first time they are often also given an anti-nausea agent such as gravol

Decrease levels of sex hormones

• reduction in sex drive in men and women

• stops menses in women

• atropy of secondary sexual characteristics in men

Effects on Eyes

• constriction of pupil

• mechanism unknown

Gastrointestinal Effects

• diminish peristalsis in intestine

• increase muscle tone in intestine

• above two effects lead to constipation

• decrease movement of material in intestine and subsequently fecal dehydration and constipation

Pyschological Effects

1. euphoria

2. dysphoria

3. decreased concentration

4. dulling of emotional pain

Euphoria

mediated via delta receptors; brought about via indirect activation of dopaminergic neurons projecting to nucleus accumbens

Dysphoria

• sometimes seen with first usage, for some people, dysphoria is always seen with particular opiates

• seems to be mediated via sigma receptors

Decreased concentration

• likely secondary or partly due to the sleepiness these drugs produce

Dulling og Emotional Pain

• mediated thru opiate receptors (primarily mu) in limbic system and frontal love

Tolerance

• Develops to: respiratory depression, analgesic, sedation, euphoria

• may develop to: pupil constriction

• does NOT develop to: constipation

• regular weekend user- tolerance will develop in approx. 1 year

• with daily use; develops within about 8 to 10 days

• with development of tolerance, consumption will increase 10-fold; doses taken by a regular user may be sufficiently high to kill a novice

• mechanisms responsible for tolerance

  • increase in # of enzymes (pharmacokinetic)

  • changes in receptor densities (pharmacodynamic)

  • cross tolerance with other opiates and alcohol

Physical Dependence

• characteristic withdrawal

• restlessness and agitation, yawning appears, fever and chills, deep sleep, cramps v/d, twitching of limbs, profuse sweating

• symptoms intensify to a peak (36 to 72 hours); over in 5 to 10 days

• withdrawal not typically life threatening

• can develop within 2 weeks with daily use

• starts with craving for the drug at about 4-6hours after last use of the drug, and then following this a number of physical symptoms will be seen, other symptoms: tearing, running nose, extreme anxiety, irritability, spontaneous ejaculation, orgasm

• for some, mild physiological changes increases in bp, hr can last for about months

• for some, there will be loss of body weight and fluids

• for some hallucinations will be seen (Likely due to high dever)

• with recent increase in drug purity, withdrawal symptoms are more intense than 30 years ago

Psychological Dependence

• more difficult to treat than physical dependence

• some success seen with Methadone and other synthetic opiates (e.g., LAAM, buprenorphine)