Pharmacology 203 Opioids Opioid Analgesics The treatment of severe pain The American Academy of Pain Medicine reports: >100 million Americans in chronic pain, and that more than 50% of hospitalized patients die in pain. Why? It turns out that pain is hard to treat Sensory Neurons Proprio-receptors Muscle spindles are large, fast, myelinated fibers that dominate transmission routes and spinal relays. Merkel, Meissner, Pacinian, Ruffinii Touch or pressure receptors that are slightly slower & smaller but still myelinated and dominant. Aδ Free nerve endings for temperature and pain. They are thin but mylenated and transmit initial, sharp pain signals. “C” fibers Unmylenated free nerve endings. Slow and unspecialized; transmit pain, itch, aches. Morphine, from Morpheus, the Greek God of dreams. Heroin, diacetylated morphine, from “Hero,” as in, what a great drug. Nociception often causes autonomic effects apart from conscious pain It is common to experience the effects of sympathetic stimulation, especially along with severe pain. Signs and symptoms of SNS recruitment include: • Pallor • Diaphoresis • Tachycardia and increased blood pressure • Syncope • Nausea and vomiting • Anxiety However, activation of the sympathetic nervous system should suppress the sensation of pain, which may be why alpha-2 agonists are useful in the treatment of chronic pain.
Transcript
Pharmacology 203 Opioids
Opioid Analgesics The treatment of severe pain
The American Academy of Pain Medicine reports: >100 million Americans in chronic pain, and that more than 50% of
hospitalized patients die in pain. Why?
It turns out that pain is hard to treat
Sensory Neurons Proprio-receptors
Muscle spindles are large, fast,
myelinated fibers that dominate transmission routes and spinal relays.
Merkel, Meissner, Pacinian, Ruffinii
Touch or pressure receptors that are
slightly slower & smaller but still myelinated and dominant.
Aδ
Free nerve endings for temperature and
pain. They are thin but mylenated and transmit initial, sharp pain signals.
“C” fibers
Unmylenated free nerve endings. Slow
and unspecialized; transmit pain, itch, aches.
Morphine, from Morpheus, the Greek God of dreams.
Heroin, diacetylated morphine, from “Hero,” as in, what a great drug.
Nociception often causes autonomic effects apart from conscious pain It is common to experience the effects of sympathetic stimulation, especially along with severe pain. Signs and symptoms of SNS recruitment include:
• Pallor
• Diaphoresis
• Tachycardia and increased blood pressure
• Syncope
• Nausea and vomiting
• Anxiety
However, activation of the sympathetic nervous system should suppress the sensation of pain, which may be why alpha-2 agonists are useful in the treatment of chronic pain.
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Pharmacology 203 Windward Community College
Effects of opioids µ receptor effects:
• Analgesia
• Altered smooth muscle tone
• Sedation
• Mood alteration
• Nausea and vomiting
δ receptor effects:
• Delayed GI transit time
κ receptor effects:
• Central analgesia
• Delayed GI transit time
• Visceral antinociception (analgesia in the viscera)
Neuropathic pain Neuropathic pain occurs when nerves become electrically unstable and fire randomly or inappropriately. Types:
Tolerance to opioid effects A patient is considered to be “opioid naïve” if they have been taking a given opioid at a given dose for less than one week. Note that refers to both the specific opioid and specific dose!
Tolerance develops after about a week to some of the opioid effects including sedation, euphoria (or dysphoria in those
unlucky individuals), nausea and vomiting, and importantly, RESPIRATORY DEPRESSION. No tolerance develops to
constipation!!
Technically, if you titrate a patient up, there is NO UPPER LIMIT for opioid dosing.
Practically, people routinely accidently OD and die taking prescription opioids!
In the 1500’s Paracelsus, the “father” of modern pharmacology, wrote about small black pills
called “Stones of Immortality” which were made of opium, citrus juice and gold. They were used as analgesics, or pain pills, and the opium used
in them came to be known as laudanum.
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The Opioids Opiates are the opioids derived directly from the poppy plant. This includes morphine, codeine, papaverine and thebaine. From thebaine and codeine, the semi-synthethic opioids are made, including hydrocodone. Based on the chemistry of opiates, the synthetic opioids have been created, including fentanyl, meperidine and methadone. This also includes that opioid antagonists, naloxone and naltrexate.
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Morphine has been used for two centuries. It was first purified from opium around 1805 in Germany, and it would be the German Pharmaceutical giant, Merck & Company, that would commercialize its use as an analgesic. Morphine gained in popularity after the hypodermic needle was invented in 1857. It was yet another German chemist, this time working for Bayer, whose fascination with aspirin led him to try the same chemistry with morphine and which resulted in the creation of heroin.
The opioids have a number of useful properties. They suppress cough, so are used as antitussives. They cause constipation, which is a huge problem when they are used for other purposes, but which is exploited in anti-diarrheal products. They have good to excellent analgesic properties and may induce euphoria which can help alleviate the unhappiness associated with chronic pain.
Morphine (MS-Contin, Duramorph, etc.) is used extensively to treat moderate to severe pain of both an acute (like a heart attack) or chronic (like cancer) nature. It is also commonly used in delivery devices called Patient-controlled Analgesia (PCA) devices that allow the patient to self-administer their pain medications as they need it – which greatly reduces their overall need for medication.
Use care when using dailymed to search for morphine containing products, because a search for “morphine” will return results for apomorphine, which is not morphine at all!!
Hydrocodone is always compounded with something like atropine (homatropine) or acetaminophen in the United States. Hydrocodone compounded with acetaminophen is sold as Vicodin, compounded with homatropine it is sold as Hycodan and Tussigon. Compounded with chlorpheniramine (a 1st generation antihistamine), it is called Tussinex, with aspirin it’s called Lortab and with ibuprofen it’s called Vicoprofen. There are many, many other trade names for these combinations, as well as other combinations and lots of generics. Compounded hydrocodone is one of the top five selling drugs in the United States.
Go to dailymed to see the long list of products containing hydrocodone.
Diphenoxylate (Lomotil) is an opioid agonist, which at low doses is really useful to treat diarrhea (really well). At higher doses, it will get into the CNS and cause all the normal opioid effects. Therefore, to prevent abuse, the FDA requires it be compounded with atropine, much like hydrocodone is co-compounded.
Since the atropine is also constipating, this combo works together as an anti-diarrheal.
A similar opioid is Loperamide (Imodium), which like Diphenoxylate is a very effective treatment for diarrhea. We will cover Loperamide in the GIT lecture. Loperamide is a p-glycoprotein substrate, so it does not cross the blood brain barrier.
In the 1600’s, English apothacaries compounded opium (laudanum), sherry or
other wine, with herbs to create pills and syrups used for many ailments.
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Continued from page 3
Fentanyl (Duragesic, Sublimaze, and others) is a potent, synthetic opioid analgesic derived from piperidine, as are Meperidine, Diphenoxylate and Loperimide. All of these opioids are structurally very different from Morphine.
Fentanyl, like Morphine, has a short duration of action for an opioid, usually around 7 hours. This makes fentanyl (and morphine) good for something called “breakthrough” pain. When you have chronic pain, the subjective experience of that pain varies throughout the day or week, with episodes of acute pain that aren’t controlled by the level of medication that will obliterate the “normal” pain. With its high potency, rapid onset and short duration, fentanyl is an excellent choice to use occasionally to control breakthrough episodes of pain.
Meperidine (Demerol) has an even shorter duration of action, about ½ of morphine or fentanyl, but meperidine is metabolized to a neurotoxin that increases the risk of seizure. Therefore, it is only for acute pain therapeutics.
Methadone (Dolophine, Methadose), on the other hand, has an extremely long, and unpredictable duration. Lots of polymorphic P450s metabolize methadone making individual variation enormously important. Since Methadone can cause fatal respiratory depression with the 1st (or any subsequent) dose, this is NOT a drug for the opiate naïve. In fact, a major part of its usefulness is in the treatment of opioid addicts. It is that long duration also makes it very useful to treat chronic pain (but NOT FOR BREAKTHROUGH PAIN).
Methadone and propoxyphene (discontinued) are not structurally like morphine or fentanyl. These structural differences between the 3 groups of opioids means that if someone has a true, immune-mediated allergy to one, it is unlikely they will have a reaction to an opioid from a different class. For some reason, though, morphine and meperidine are the two most likely to cause opioid-induced Mast cell degranulation (histamine release) leading to severe itching (pruritus) – which is NOT an allergic reaction.
Gate Control Hypothesis
Why do alternative pain alleviation techniques, like
massage, work?
You know they do. If you strike your elbow, hitting your funny bone, you know it is anything but funny! You automatically rub your elbow and it feels better.
The initial, sharp pain is carried by fast, myelinated fibers, but the throbbing ache, is carried by unmyelinated “C” fibers. The “C” fibers can be over-ridden by signals transmitted by myelinated fibers.
When you rub, or massage, a tissue, you are activating large, myelinated fibers that transmit information about pressure. These large fibers are meant to carry much more important information so their signal takes precedence at relays in the spinal cord where peripheral sensory nerves enter the CNS.
This effectively is like closing a gate on the “C” fiber transmission.
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Buprenophine (Buprenex, Suboxone) has mixed effects at the opioid receptors. It is a C-III, mixed agonist and antagonist with a very long duration of action and considerable metabolic variability.
Pentazocine (Talwin-NC), when given orally, is always compounded with naloxone (an opioid antagonist) to prevent abuse. Like buprenorphine, Pentazocine is a mixed agonist antagonist, but it has an extremely short duration of action, lasting only 2-3 hours.
The oral formulation contains naloxone, because unlike naltrexone, naloxone is not absorbed orally. This means if someone grinds up a tablet of Pentazocine and injects it (in an attempt to get high) the naloxone will block the opioid effects. If they take it orally, as directed, the naloxone will have no effect.
Tramadol (Ultram) is really different; it isn’t an opium derivative or a semisynthetic derivative of morphine or thebaine. It actually is not just an opioid agonist, but also acts as a norepinephrine and serotonin reuptake inhibitor (giving it antidepressant effects).
Unfortunately, tramadol does cause seizures in up to 50% of patients. And probably because of the effects it has on NE and 5-HT levels, it is a suicide risk.
Dextromethorphan (DM, DXM) is an OTC antitussive found in 100’s of cold products.
The last drug in this part is Naltrexone (ReVia). Naltrexone and Naloxone (Narcan) are opioid antagonists. Naloxone is used primarily as a reversal agent to counter opioid overdose. It has a very short duration of action, though, only about an hour, so multiple courses will probably be necessary. However, there is no oral formulation.
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Naltrexone (ReVia) is available as both an enteral and a parenteral. It has a much longer, though highly variable duration of action. It is normally used in addiction treatment programs (because it can be taken orally and has a long duration of action). It is used to treat both alcohol and opioid addiction. The problem with Naltrexone is that it can cause liver damage. While it does not appear to be a hepatotoxin at therapeutic doses, there is a narrow therapeutic margin of approximately 5X.
Important things to know about the reversal agents for the opioids:
1. They will precipitate withdrawal symptoms in addicts;
2. If the half-life is shorter than the opioid, more than one course of therapy may be necessary.
(continued)
A vegetable “elixir” of opiates, herbs and alcohol created in the 1840’s in Rhode Island, but marketed around the world by missionaries.
Pharmacology 203 Windward Community College
Paregoric (camphorated tincture of opium) versus opium tincture Paregoric has been used since the early 1700’s as an analgesic and anti-diarrheal. It is also known as camphorated tincture of opium and is an oral elixir that contains 0.4 mg/mL of anhydrous morphine as the main ingredient (along with alcohol, glycerin and benzoic acid).
It is VERY IMPORTANT to not confuse paregoric with OPIUM TINCTURE, tincture of opium, or deodorized tincture of opium because these products typically contain 10 mg/mL of morphine.
In other words, given the same volume, the amount of opiate extract present in these products are 25-fold higher than that of the paregoric.1
1. Paraphrased from: Opioid Analgesics and the GIT. LN Chan. Nutrition Issues in
Gastroenterology, Series #64, Practical Gastroenterology. P 37-50. August 2008.
There are records of the opium poppy, called the “joy plant,” being cultivated
3400 years ago in Mesopotamia
All images, except the photo of the author with her much beloved dog, are from the National Library of Medicine image collection.
Homework and Exercises 1. Read the “START HERE” announcement in Laulima for updates and instructions.
2. Read about Opioids in Chapter 29, Pharmacology of Severe Pain and Migraines. Adams & Urban, PHARMACOLOGY Connections to Nursing Practice.
3. Review the Powerpoints and listen to the audio from the face-to-face lecture. You may opt to watch the appropriate videos for this lecture. Review any handouts available for this lecture in the Course Index.
4. Complete the SLO practice set for Opioids in Assignments, Tests and Surveys.
5. Use “Chat,” “Discussions and Private Messages” or the lecture “Forum” to ask questions and find answers or to seek assistance.
6. Complete the online quiz in Laulima, Assignments, Tests and Surveys.
