Opium, opiates and synthetic opioids Flashcards

Question

Purdue Pharma and OxyContin

Answer 1

OxyContin was introduced by Purdue Pharma in 1996 as an ‘extended release’ form of oxycodone. It had a duration of action of 12h, which was promoted as an advantage as it reduced the number of daily doses required. FDA consideration of the 1995 application suggested no advantage over 4x daily oxycodone. Numerous randomised concentration-controlled trial (RCCT) studies agreed with this. OxyContin was aggressively marketed to healthcare professionals, particularly in industrial cities with predominantly white populations. Its sales grew from $48 million in 1996 to almost $1,1 billion in 2000. The high availability of OxyContin correlated with increased abuse, diversion, and addiction. By 2004, OxyContin had become a leading drug of abuse in the United States. The lifetime prevalence of addictive disorders has been reported at 3-16% in the general population, and studies in the use of opioids in chronic pain management indicate levels of addiction between 10-45%. However, Purdue representatives were trained to describe the risk of addiction as less than 1%, citing reports of opioid use in therapy for ACUTE pain. Purdue also provided incentives to HCP, staff and more to promote the drug. This included >40 all-expenses-paid conferences in resorts recruiting >5000 healthcare workers between 1996 and 2000. Purdue also distributed patient starter coupons for OxyContin for a free limited-time prescription for a 7-30 day supply, and 34k were redeemed by 2001. HCP were treated to OxyContin merchandise including fishing hats, stuffed plush toys, and music compact discs at levels unprecedented for a schedule II opioid. In 2001, a Purdue sales representative had an average salary of $55k, with annual bonuses ranging from $15k to nearly $240k. Total sales incentive bonuses for Purdue sales reps were $40 million. Purdue’s marketing plan involved nationwide prescriber profiles on individual physicians. By 2003, nearly half of all physicians prescribing OxyContin were primary care physicians. It is debatable weather these physicians were properly trained to deal with chronic pain management or addiction, or if they had sufficient time or evaluation/follow-up on complicated chronic pain sufferers.

Answer 2

In 1952, the Sackler family (three medic brothers) bought the Purdue-Frederick company, which made a tonic compound made with sherry and glycerin. The Sackler family donated millions to art museums and Universities, but in 1987, Arthur, the art investor, died and the two brothers picked up the company from his estate and changed it to Purdue Pharma. Their aggressive marketing of opioid medication caused some backlash from members of the public. In 2015, Prescription Addiction Intervention Now Sackler organization (PAIN Sackler) demanded that public institutions remove Sackler insignia from their premises and refuse future funding. In 2016 PAIN Sackler and other advocacy groups called upon the Sackler family to devote their $13 billion fortune to rehabilitating patients. By 2019, the National Portrait Gallery in and Tate Modern in London, and the Metropolitan and Guggenheim in New York City all publicly renounced Sackler funding.

Answer 3

The constraints on OxyContin prescription drove people to seek opioids from other sources. Fentanils and nitrazenes became popular in the US. Fentanils and nitrazenes are high potency and efficacy opioid agonists. Carfentanil has 10,000x morphine’s potency. It is used in veterinary rather than human medicine. It can also be found in adulterated heroin samples to give it a ‘kick’ The 2002 Moscow theatre hostage crisis was a seizure of the crowded Dubrovka Theater in Moscow by Chechen terrorists. Security services flooded the area with carfentanil to try to sedate the terrorists, but this killed all 40 hostage takers and 132 out of 912 hostages. Etonitazene has 10,00x morphine’s potency and it is also found in adulterated heroin samples.

Answer 4

In vitro, G protein-coupled receptors signal through multiple pathways. Agonists can favour one signalling pathway over others, showing bias. However, aligning particular pathways in vitro with effects in vivo hasn't been done convincingly so far. Oliceridine was claimed as a G protein-biased agonist - biased for G-protein activation rather than ꞵ-arrestin recruitment, compared to morphine. This mechanism is thought to decrease the development of tolerance and degree of respiratory depression, though evidence on this topic is conflicting and the opposite has also been suggested. - Papers in 1999 and 2000 found that knocking out arrestin sustained the analgesic effect of morphine, so tolerance did not develop as quickly. - In 2005, they found that the degree of respiratory depression caused by morphine was also reduced. - This led to the theory that the G-protein pathway controlled analgesia, while the arrestin pathway was responsible for side effects. - However, other groups found that if you knock out arrestin, mice still suffer from respiratory depression, and that this may actually be mediated by the G-protein pathway. - Another paper actually found that, by analysing opioids that caused overdose, some of the more deadly compounds are very efficacious in the G-protein pathway and only partially efficacious in the arrestin pathway. Olicerdine gained FDA approvel in 2020, but its action as a biased agonist is controversial and it may be just a partial agonist.

Answer 5

The Office for National Statistics (ONS) reports that methadone causes the majority of opioid-related deaths in the UK. In 2024, it caused ~700 deaths. The UK process of drug compound purchase is more centralised than in the US, so we have less of an issue with the use of ultra-potent agonists like fentanyl.

Answer 6

Loperamide, an over-the-counter antidiarrheal medicine, is a potent MOR agonist approved by the FDA. It has been on the market since 1976 and is relatively safe with no central nervous system-related side effects when used for a short period of time at the recommended therapeutic dose (2-8 mg/day). In recent years, loperamide has become notoriously known as the "poor man's methadone" for people with substance dependence due to the increase in loperamide overdoses from self-administered medication to treat opioid withdrawal symptoms. As a result, in 2018, the FDA decided to limit the available packaged dose of loperamide to stop prominent abuse.

Answer 7

Fentanyl is a potent synthetic MOR agonist used medically for acute and chronic pain, breakthrough pain in cancer and as an anaesthetic adjuvant due to its analgesic and euphoric effects. It was first synthesized in 1960 by Dr. Paul Janssen in Belgium. It is 75-100x more potent than morphine, which makes the risk of overdose higher. Illicit fentanyl is often added to heroin, and fentanyl-laced cocaine and marijuana samples have also been reported, increasing the risk of overdose among unsuspecting users. Several FDA-approved fentanyl analogues, such as sufentanil, alfentanil, remifentanil and carfentanil, were developed in the 1960s for medical and veterinary purposes. Illicit fentanyl analogues have emerged due to the simplicity of their synthesis, creating significant regulatory challenges Fentanyl and its analogues are also to bind to VGSCs and serotonin receptors, although their effects at therapeutic concentrations are unclear. Carfentanil is ultrapotent, estimated to be 20-100x more potent than fentanyl and about 10,000x more potent than morphine, so its use is largely restricted to tranquilisation of large animals in veterinary medicine. It is not approved for human use. Lethal dose in humans is far less than 1 mg. Carfentanil has emerged as a problematic contaminant in other drugs of abuse. It is used as a cutting agent for less potent opioids such as heroin. It is suggested that fentanyl is biased toward the β-arrestin recruitment pathway, however, there is no information on whether carfentanil exhibits the same bias.

Answer 8

Bucinnazine is a synthetic opioid first synthesised in Japan in the 1960s. It is not currently approved for clinical use or scheduled in the US. It primarily binds MORs but may also interact with dopamine, serotonin, and noradrenaline neurotransmission. It is a weak opioid receptor agonist and is considered a moderate to weak analgesic, with an analgesic effect ~1/3 of that of morphine. It is also thought to be less addictive than morphine.

Answer 9

Krokodil is a cheap, homemade substitute for heroin, primarily used in Russia and Ukraine, with the main active component being desomorphine, an opioid 10x more potent than morphine. Also known as “Russian magic”, “croc”, or “krok”. The homemade synthesis of krokodil involves extracting codeine from tablets and reducing it to desomorphine using readily available materials. The process is dangerous and results in a corrosive mixture with low pH due to the presence of acids. Its name comes from the scaly, ulcerated skin seen in users, resembling a crocodile, and also from α-chlorocodide, an intermediate in desomorphine synthesis. Krokodil emerged in the media around 2008 as a "flesh-eating drug", causing ulcers, gangrene and potential limb amputation. Systemic effects include neurological damage, endocrine issues, and organ damage. Desomorphine was previously available as a pharmaceutical but was discontinued due to its short duration of action and high toxicity. Krokodil users report devasting health effects and often die within 2−3 years after their first use. They need to be monitored not only for opioid overdose symptoms but also for specific symptoms associated with the presence of phosphorus and iodine due to contaminants. Ironically, the properties that make krokodil so dangerous might allow for the development of new clinical analgesics. In addition to the toxic effects, animals exposed to krokodil presented high pain tolerance for the corrosive and necrotizing effects caused by krokodil, suggesting the synergic effect of other morphinans present in krokodil besides desomorphine.

Answer 10

U-47700, also known as "Pink," "Pinky," "U4," or "fake morphine", is a novel synthetic opioid (NSO), discovered by the Upjohn company in the 1970s. It is 10x more potent than morphine. It has become a drug of widespread abuse due to its ease of synthesis and, until recently, the lack of robust detection methods. U-47700 has been found in counterfeit oxycodone tablets and is a key ingredient in "gray death", a potent mixture of synthetic opioids. It is now a schedule I drug. U-47700 was found to have contributed to the death of the artist Prince.