Opioids Lecture Notes PDF

# The Opiates ## Definitional Issues - Naturally occurring, derived, and synthetic compounds with analgesic properties. - Often referred to as "narcotic analgesics". - The term "narcotic" re: opiates can be confusing as it categorizes the opiates with dissimilar drugs. ## Naturally Occurring - M...

# The Opiates ## Definitional Issues - Naturally occurring, derived, and synthetic compounds with analgesic properties. - Often referred to as "narcotic analgesics". - The term "narcotic" re: opiates can be confusing as it categorizes the opiates with dissimilar drugs. ## Naturally Occurring - Morphine, codeine, and thebaine are found in opium. - Opium is the sap from seedpods of the opium poppy. - Morphine: 10% - Codeine: 0.75 to 2.5% - Thebaine: < 1% - 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. - Milky white juice oozes out (this is the raw opium). - Over a day, this substance hardens (oxidizes), becomes reddish brown, or dark brown, and is heavy like syrup; forming small gumlike balls that look like tar, taste bitter, and smell like new mown hay. - As noted in McKim, the opium is produced for an average of 10 days after petal drops. - The substance is collected. ## Opiate Derivatives/Semi-Synthetics - **Heroin** - **Other Examples:** - Hydromorphone - Oxycodone - Oxymorphone - Hydrocodone - Slight changes to chemical composition. - E.g., heroin Derived by adding acetyl groups to morphine molecule (3x more potent than morphine). - More lipid soluble than morphine. - **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. - More potent than morphine. - **Hydromorphone (Dilaudid)** ## The Opiates Synthetic - **Meperdine** - Commonly prescribed pain-killer, less potent than morphine. - **Methadone** - Used to treat chronic pain and opiate dependency; as potent as morphine re: analgesic effect, less potent as morphine re: euphoric effects. - **Other Examples:** - Fentanyl - LAMM - Buprenorphine, - **Fentanyl** - Marketed as Sublimaze in the 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. - Smoked, injected, orally administered. - **Street use of fentanyl is being preferred over street use of heroin.** Reasons given by users include: - Greater rush. - Cheaper. - Greater availability. - Healthier; decreased risk of blood borne viruses, decreased skin abscesses. - Smoking involves heating powder and inhaling video. ## Opiate Antagonists - Useful in treating overdoses. - **Naloxone** - Brand name is Narcan. - Can be given IV or IM. - Competitive antagonist at mu, 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. - Different from naloxone in that it has some mild agonist morphine-like effects. ## Uses - Medical uses include: - Treatment of pain. - Treatment of diarrhea. - Treatment of cough. - They have been used for these three purposes for hundreds even thousands of years. ## Uses and History - Medical use dates back hundreds of years. - Documented in Egyptian medical scrolls dating back to 1550 BC. - In second century AD, Galen recommended it for practically everything. - **In 1520, medicinal drink called laudanum was introduced.** - A physician named Parcelsus, introduced a medicinal drink combining opium, wine and an assortment of spices, which he called laudanum. - **Picture** - As you can see in this picture, in some formulations, laudanum had about 45-46% alcohol and about 65 mg of opium (typically morphine), in other formulations, there would be more opium e.g., 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 Pennsyworth of Peace - **Picture:** - Now Paracelus, like Galen, recommended laudanum for practically every known disease and it was taken for a variety of reasons. - Women in the 18th century, for example, were prescribed it for menstrual pain and melancholy. - Following in the footsteps of Egyptians, mothers would give it to their children to keep them quite or to treat colic, as noted in this slide, - And some people took it for toothache - and unfortunately, for at least one individual in the 1800s (1880) - The initial use of it as a toothache remedy lead to an addiction to opium, this individual was a 20-year-old man in the 1800s, by the name of Thomas DeQuincy, who then later wrote about his first experience with opium, as described here: -"I took it; and in an hour, O heavens! what a revulsion! what a resurrection, from its lowest depths, of the inner spirit! what an apocalypse of the world within me! That my pains had vanished was now a trifle in my eyes: this negative effect was swallowed up in the immensity of those positive effects which has opened before me; in the abyss of divine enjoyment thus suddenly revealed; Here was a panacea.... for all human woes; here was the secret of happiness, about which philosphers had disputed for so many ages, at once discovered; happiness might now be bought for a penny; and carried in the waistcoat-pocket; portable ecstasies might be corked up in a pint-bottle; and peace of mind could be sent down by the mail" -DeQuincy, T. Confessions of an English Opium Eater - **Now, in addition to being used medically for hundreds, opium has been used recreationally for hundreds of years as well.** ## Uses and History - 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. - **Picture** - 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. - Third erpons from the front has a pipe in his mouth and is showing the reclining position that people would need to take - the position and types of pipes are illustrated somewhat better in the images in this next slide. - **Picture** - As you likely know, opium dens are establishments where people went to buy smoke and then enjoy the effects of opium as seen in the next slide because. - Most opium dens kept a supply of opium paraphernalia such as the specialized pipes and lamps that were necessary to smoke the drug. - Patrons would recline in order to hold the long opium pipes over oil lamps that would heat the drug until it vaporized, allowing the smoker to inhale the vapors. - 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 United States, particularly on the West Coast, there were opium dens that mirrored the best to be found in China, with luxurious trappings and female attendants. - For the working class, there were also many low-end dens with sparse furnishings. These latter dens were more likely to admit non-Chinese smokers.[1] - **Additional Notes:** There are references, indication of opium use prior to the 2nd C.e.g., a ceramic opium pipe dating to the Bronze Age was found in Cyprus, as noted in your text, there is written reference to. - **Picture:** - The reclining would be needed to hold the long opium pipes over oil lamps. - Opium dens were frequented by all levels of society, and their opulence or simplicity reflected the financial means of the patrons. ## History - Up until early to mid 1800s, opium use was widely socially accepted and not perceived as a social or medical problem despite large number of individuals being addicted. - Mid to late 1800s saw some governmental efforts in US and Britain to regulate use and selling of drug. - Due to concern about negative consequences of chronic opium use or anti-Chinese prejudice? - Now, for many years, opium was not a controlled substance and was widely available for both medical and recreational use (although as your textbook notes, there was some control on morphine beginning in the 1800s, which was around the time it became available). - And use of it was socially acceptable – particularly the use of landanum or what was referred to as “opium drinking”. - As your textbook notes, it was not considered to be a medical or social problem - despite the fact that one source indicates that a very conservative estimate is that 250, 000 people in the US alone were addicted to some type of opiate. - It wasn't until the mid to late 1800s, that In 1860s and 70s, that here were some governmental efforts to gain control over the drug in Britain and the US. - And 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_. - One of the governmental efforts was a city law passed in In 1875, San Francisco which outlawed opium dens and a newspaper at the time quoted: ## History - **San Francisco Newspaper Quote:** - "...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" - Interestingly, as one drug historian noted, no mention was ever made of any moral ruin coming out of drinking at home." - **Addl note:** The other governmental action was a parliamentary bill in the Britain in 1868 which made pharmacists shops the only legal source of opiates. - **History:** - After this, a slight change was made inside Canada's Fort Augusta. - **Canada: Opium Act, 1908:** prohibited the "importation, manufacture, and sale of opium for other than medicinal purposes". - **Canada: Opium and Narcotic Act, 1911:** prohibited the "improper use of Opium and other drugs" - **Canada CISA 1996. 10V** - **Where they do not to screw us.** - **Opium Act, 1908:** - Now, regardless of the reason, in the early 1900s more and more restrictions were placed on the selling, dispensing and use of the opiates and on July 10, 1908, a Bill (C 205) was passed by our government in the House of Commons that. - Now although it also prohibited the use of opium by smokers, the act was aimed at dealers vs user and so was followed up by. - **[1] The motion was adopted without debate. The Minister introduced Bill 205, An Act to prohibit the importation, manufacture and sale of opium for other than the medicinal purpose. (Opium Act, 1908).[25] The first section of the Act prohibited the importation of opium without authorization from the Minister of Customs. Additionally the drug could be used for medical purposes only. The manufacture, sale and possession for the purpose of selling crude opium or opium prepared for use by smokers was also prohibited. Whoever violated these provisions could be found guilty of a criminal offence punishable by a maximum prison term of three years and/or a minimum fine of $50 and not exceeding $1,000. Even though it prohibited the use of opium, the legislation was aimed at opium dealers, most of whom were Chinese, and not users. The bill was given Royal Assent on July 20, 1908.** - **The Opium and Narcotic Drug Act, 1911:** - The enactment the Opium Act led to the introduction of 8 new bills intended to make it both more restrictive and effective on January 26, 1911, Mackenzie King, who had just become the Minister of Labour, introduced Bill 97, an Act to prohibit the improper use of Opium and other Drugs (the Opium and Narcotic Drug Act, 1911).[26] - During the deliberations on second reading, Mackenzie King gave three reasons for introducing the bill: the Shanghai Commission, the panic in Montreal caused by cocaine use and the need to grant special powers to the police to ensure that the Act could be enforced effectively. The Shanghai Commission had adopted a number of non-binding resolutions, including: putting a gradual stop to the opium smoking habit, with due regard to the specific circumstances of each country; prohibiting the use of opium and its alkaloids and derivatives (morphine, heroin, etc.) and other drugs for non-medical purposes; and prohibiting the export of these substances to countries that prohibited their use. - No member raised any objections about the four drugs added to the Schedule to the Act, namely cocaine, opium, morphine or eucaine. Section 14 of the Act also 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 in society, it would be possible to add it. ## MOA - Opiates will be administered: - Orally - opium eating. - Parenterally - intramuscularly, subcutaneously (skin popping), intravenously (mainlining). ## Distribution - High concentrations in lungs, liver, spleen. - Readily passes through the placental barrier. - In the brain, concentrated in the limbic system: - Basal ganglia. - Nucleus accumbens. - Ventral tegmental areas. - Periaqueductal 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 most understood. - Decrease rate of neuronal firing via two mechanisms: - Inhibiting Ca influx: thus decreasing or stopping release of NE, DA, Ach in the presynaptic neuron (does this via opiate receptors on the 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). - Other three receptors: sigma, episolon, and lambda. - Mu receptors: distributed throughout the limbic system. - Delta receptors: distributed throughout the limbic system, but their distribution does not overlap with mu receptors. - Kappa receptors: found in the nucleus accumbens, ventral tegmental area, the hypothalamus, and thalamus. - Strong attachment vs strong effect: some opiates have weak attachment but strong effect, others the opposite e.g., morphine at mu receptors have weak attachment (easily dislodged) but strong effect. - Not all functions of the receptors are known. ## CNS Effects - Analgesic Effects - Depress respiratory center. - Suppress cough center. - Depress vomitting 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 the 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 the limbic system and frontal lobe. - **RE: 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 Graval. - **RE: Decrease levels of sex hormones:** - Reduction in sex drive in men and women. - Stops menses in women. - Atrophy 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 the intestine and subsequently fecal dehydration and constipation. ## Psychological 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 the nucleus accumbens. - **Dysphoria:** sometimes seen with first usage, for some people, dysphoria is always seen with particular opiates. - **Dysphoria:** seems to be mediated via sigma receptors. - **Decreased concentration:** – likely secondary or partly due to the sleepiness these drugs produce. - **Dulling of emotional pain** mediated through opiate receptors (primarily mu) in the limbic system and frontal lobe. ## Tolerance - Develops to: - Respiratory depression. - Analgesic. - Sedation. - Euphoria - May develop to: - Pupil constriction. - Does NOT develop to: - Constipation - Develops rapidly. - Three types: - With intermittent use, characterized by sprees alternating with drug-free periods little tolerance develops. - 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. - Pupil constriction tolerance is rare. - 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 to10 _days_. - Withdrawal not typically life-threatening. - Can develop within 2 weeks with daily use. - Starts with a craving for the drug at about 4-6 hours 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 like increases in bp, hr can last for about 6 months. - For some, there will be loss of body weight and fluids. - For some hallucinations will be seen (likely due to high fever). - 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).