The Opioids I: Poppies, Pain, & PharmK

Poppies: Opium, Opiates, Opioids

• Papaver somniferum (“sleep”) is the plant source of all natural opiates (e.g., opium, morphine, codeine - derived directly from plant)

• Opium: waxy resin from seed pods of the plant

• Long History of medium, ritual use

  • Sumerians (3400 BCE) called it the “joy plant”

  • used medicinally in Ancient Greece (e.g., Hippocrates), Rome

• Effects: analgesia, reduced body awareness, euphoria, anxiolysis, sedation; antitussive (cough), anti-diarrheal

• Side Effects: depressed respiration, nausea/vomiting, pupil constriction (“pin-point” pupils → parasympathetic effect)

4 main opium poppy alkaloids & synthetic derivatives

• Natural Opioids (“Opiates”)

  • derived from the poppy Papver somniferum → opium, morphine, codeine

• Semi-synthetic

  • synthesized from naturally occurring opium products → heroin, hydrocodone, oxycodone

• Synthetic Opioids

  • made entirely in a lab environment → methadone, tramadol, & Fentanyl

Opiates: Modern History

• 1800s: OTC opiate medicines, pills, syrups sold for variety of ailments

  • laudanum: opium, wine & spices mix was very popular among Victorians

• 1844: Hypodermic needle invented

• 1861-1865: American Civil War → opium & morphine addiction becomes known as “soldiers’ disease”

• 1900: “Opium dens” & OTC access led to estimated 4% of US pop. addicted to opium or morphine

• 1914: Harrison Narcotics Act 

  •  strictly regulates & taxes most opiate & coca products

  • non-medical uses banned

Opiates: The Birth of Heroin

• 1908: Bayer Co. (Germany) creates diacetylmorphine, marketed as “Heroin”

  • acetyl groups → increase heroin’s lipid solubility, passing through BBB more rapidly than morphine

Opioid Metabolism (flowchart)

• Heroin → 6-MAM* → Morphine → morphine-6-glucuronide (active)

• Codeine → Morphine → morphine-6-glucuronide

• Codeine → Hydrocodone

• get turned into morphine in process of being metabolism & inactive

Opiates: PharmK

• Administration & Absorption

  • IV most common (esp. heroin @ 3x more potent than morphine), can also be oral, nasal, smoked

  • GI tract absorption is slow & incomplete

  • purity → become more white → more pure

• Distribution

  • morphine: Schedule II, less lipid soluble, slowly crosses BBB

  • heroin: Schedule I, more lipid soluble, quickly crosses BBB, more intense “rush” when smoked or injected

• Metabolism: 90% done through CYP enzymes

  • morphine: half-life = 3-5 hrs; metabolized to very active metabolite morphine-6-glucuronide

  • heroin: half-life = 10-20 min; metabolized to morphine (active), mono-acetylmorphine (active), others

Opioid Metabolism

• Genetic Opioid Metabolism Defect (GOMD): ~40% of pain patients have GOMD in a CYP enzyme

  • Fast metabolizers → ineffective pain management; requests for higher doses can lead to suspicion of diversion, abuse, addiction

  • Slow metabolizers → levels rise quickly can cause potentially life-threatening allergic reactions

Opioid receptors & Their Endogenous Ligands

• Endogenous Opioids: naturally-occuring peptides w/ morphine-like properties; opioid peptides (“-OP”) & receptors (“-OR”)

• Mu: MOPs (endorphins) & MORs

  • high # in dorsal horn of spinal cord, brainstem (RVM-medulla, PAG), thalamus (somata-sensory)

  • strongest analgesia effects

• Delta: DOPs (enkephalins) & DORs

  • high # in caudate-putamen & NAc

  • role in euphoric response to opioids

  • moderate analgesia effects

• Kappa: KOPs (dynorphins) & KORs

  • high # in amygdala, hypothalamus, pituitary gland

  • mild analgesia, dysphoria, disorientation

  • Salvia divinorum: psychedelic (deliriant), acts as KOR agonist

• analgesia → turn down pain messages

Opioid Receptors Located Pre- & Post-Synaptically

• post-opioid receptors: slow down flow of Ca2+ (IPSPs), increase output of K+ (IPSPs)

• pre-opioid receptors: inhibit release of NTs (inhibit secondary messengers); affect proteins from allowing vesicles to release NTs

• overall: lower brain activity

Opioid Receptors Inhibit Neural Activity in 3 ways

• Ligand binds to GPCR →

  1. supress second messengers

  2. enhances K+ flow

  3. supress Ca2+ flow 

  • ^^ inhibitory

Pain Transmission & Modulation: Gate Control Theory

• bottom-up: coming from PNS to CNS

  • Spino-thalamic Tract (ascending)

    • DRG (dorsal root ganglian) → Spinal Cord → Medulla (brainstem) → PAG (mid-brain) → Thalamus, Cortex, Amygdala & Hypothalamus (esp. Anterior Cingulate)

    • uses Substance P (what neurons are using to pass the message

• top-down: coming from CNS to PNS

  • Descending Pain-Modulation Pathways

    • Anterior Cingulate (Cortex - Amygdala & Hypo.) → PAG (produces enkephalin) → medulla (brainstem) → spinal cord => slows down/reduces amount of pain signals being sent

• Gate Control Theory of Pain: “bottom-up” pain signals pass through “nerve gates” @ spinal cord, must be open for signals to reach the brain

  • “top-down” brain modulation can open or close these gates