Yes, some individuals have genetic or physiological differences that make them less responsive—or even completely unresponsive—to opioids. Several factors can contribute to this:
1. Genetic Variability in Opioid Receptors
• The OPRM1 gene encodes the mu-opioid receptor, the primary site where opioids exert their effects. Variations in this gene can reduce opioid binding or signaling, making opioids less effective or even ineffective.
• For example, the A118G polymorphism in OPRM1 is associated with reduced opioid sensitivity in some populations.
2. Differences in Metabolism (Cytochrome P450 Enzymes)
• Opioids like codeine, oxycodone, and tramadol are prodrugs that require activation by the liver enzyme CYP2D6 to become their active forms (e.g., morphine from codeine).
• Poor metabolizers (due to genetic variants in CYP2D6) may not convert these drugs effectively, leading to little or no pain relief.
3. Increased Pain Sensitivity (Opioid-Induced Hyperalgesia or Neuropathic Pain)
• Some people experience paradoxical effects, where opioids make pain worse instead of relieving it.
• Neuropathic pain conditions sometimes do not respond well to opioids because they involve nerve damage rather than traditional pain pathways.
4. Tolerance and Receptor Downregulation
• Chronic opioid users may develop tolerance, meaning they need higher doses for the same effect. However, in some cases, receptors become so desensitized that opioids lose their efficacy entirely.
5. Psychological and Neurological Factors
• The perception of pain is influenced by brain chemistry, mood, and expectation. People with high endogenous opioid activity (naturally high endorphins) or certain psychological traits may not feel much effect from opioids.
Would you like me to elaborate on any specific factor?
It might be that you’re the type two kind of person with the problem with metabolizing opioids.
As I understand it o-dsmt is the metabolite of tramadol so it makes sense that taking that you felt something.
But hydrocodone requires breakdown in the liver
Hydrocodone is metabolized by CYP2D6, but unlike codeine and tramadol, it does not fully rely on it for activation. Here’s how it works:
• CYP2D6 converts a portion of hydrocodone into hydromorphone, which is a more potent opioid and contributes to its pain-relieving effects.
• However, hydrocodone itself is already active and binds to opioid receptors, meaning CYP2D6 metabolism is not essential for its effectiveness (unlike codeine, which must be converted into morphine to work).
• CYP3A4 also plays a role, breaking hydrocodone into less active metabolites.
CYP2D6 Variability and Hydrocodone Response
• Poor metabolizers (PMs) of CYP2D6 (those with low or no enzyme activity) may experience weaker pain relief from hydrocodone because they produce less hydromorphone.
• Ultra-rapid metabolizers (UMs) may convert hydrocodone into hydromorphone too quickly, potentially leading to stronger effects or side effects.
So while CYP2D6 contributes to hydrocodone’s potency, it is not required for the drug to work, and its analgesic effect is still present in poor metabolizers, just potentially weaker.
But it seems to me that dilaudid should have worked on you
Dilaudid (hydromorphone) does not require CYP2D6 for activation because it is already in its active form. Unlike codeine, tramadol, or even hydrocodone (which partially depends on CYP2D6 for conversion into a more potent metabolite), hydromorphone works directly at opioid receptors without needing metabolic activation.
How Dilaudid Is Metabolized
• Hydromorphone is mainly metabolized in the liver by glucuronidation (via UGT2B7) into hydromorphone-3-glucuronide, which is inactive.
• CYP enzymes, including CYP2D6, play little to no role in its metabolism.
Implications
• CYP2D6 poor metabolizers (PMs) and ultra-rapid metabolizers (UMs) will generally not experience significant differences in response to hydromorphone.
• Patients who do not respond well to codeine or hydrocodone due to CYP2D6 issues may still get effective pain relief from hydromorphone.
So my best thinking is that you have a problem metabolizing opioids in your liver.
Something like this might be true for you.
If you don’t feel the effects of hydrocodone, several factors could be at play. Here are the most likely reasons:
1. CYP2D6 Poor Metabolism (Reduced Conversion to Hydromorphone)
• Hydrocodone is partially metabolized by CYP2D6 into hydromorphone, which is more potent.
• If you are a CYP2D6 poor metabolizer (PM) (due to genetic variations), your body may not efficiently convert hydrocodone into hydromorphone, leading to reduced pain relief.
• You can get a pharmacogenetic test to check your CYP2D6 status.
2. CYP3A4 Overactivity (Rapid Breakdown of Hydrocodone)
• Hydrocodone is also broken down by CYP3A4 into an inactive metabolite.
• If your CYP3A4 activity is high, hydrocodone might be metabolized too quickly before it has time to work.
• Certain medications (e.g., rifampin, St. John’s Wort) can increase CYP3A4 activity, making hydrocodone less effective.
3. High Opioid Tolerance or Natural Insensitivity
• If you’ve used opioids before, you may have a higher opioid tolerance, requiring a stronger dose.
• Some people have naturally lower opioid sensitivity due to genetic variations in the OPRM1 gene (mu-opioid receptor).
4. Pain Type (Neuropathic Pain or Hyperalgesia)
• Hydrocodone is most effective for nociceptive pain (injury, surgery, inflammation).
• Neuropathic pain (nerve damage, fibromyalgia) often does not respond well to hydrocodone or opioids in general.
• Opioid-induced hyperalgesia (OIH) can paradoxically make pain worse instead of better.
5. Absorption and Other Physiological Factors
• If you have gastrointestinal issues (e.g., gastroparesis), your body might not absorb hydrocodone efficiently.
• Food and pH levels in your stomach can also influence absorption.
What You Can Do
• Try a different opioid: Since hydromorphone (Dilaudid) doesn’t rely on CYP2D6, it may work better for you.
• Consider non-opioid pain management: Depending on the cause of your pain, other medications (e.g., NSAIDs, gabapentinoids, SNRIs) may be more effective.
• Get pharmacogenetic testing: This can determine whether CYP2D6 or other enzymes are affecting your drug metabolism.
Yes, some individuals have genetic or physiological differences that make them less responsive—or even completely unresponsive—to opioids. Several factors can contribute to this:
1. Genetic Variability in Opioid Receptors
• The OPRM1 gene encodes the mu-opioid receptor, the primary site where opioids exert their effects. Variations in this gene can reduce opioid binding or signaling, making opioids less effective or even ineffective.
• For example, the A118G polymorphism in OPRM1 is associated with reduced opioid sensitivity in some populations.
2. Differences in Metabolism (Cytochrome P450 Enzymes)
• Opioids like codeine, oxycodone, and tramadol are prodrugs that require activation by the liver enzyme CYP2D6 to become their active forms (e.g., morphine from codeine).
• Poor metabolizers (due to genetic variants in CYP2D6) may not convert these drugs effectively, leading to little or no pain relief.
3. Increased Pain Sensitivity (Opioid-Induced Hyperalgesia or Neuropathic Pain)
• Some people experience paradoxical effects, where opioids make pain worse instead of relieving it.
• Neuropathic pain conditions sometimes do not respond well to opioids because they involve nerve damage rather than traditional pain pathways.
4. Tolerance and Receptor Downregulation
• Chronic opioid users may develop tolerance, meaning they need higher doses for the same effect. However, in some cases, receptors become so desensitized that opioids lose their efficacy entirely.
5. Psychological and Neurological Factors
• The perception of pain is influenced by brain chemistry, mood, and expectation. People with high endogenous opioid activity (naturally high endorphins) or certain psychological traits may not feel much effect from opioids.
Would you like me to elaborate on any specific factor?
It might be that you’re the type two kind of person with the problem with metabolizing opioids.
As I understand it o-dsmt is the metabolite of tramadol so it makes sense that taking that you felt something.
But hydrocodone requires breakdown in the liver
Hydrocodone is metabolized by CYP2D6, but unlike codeine and tramadol, it does not fully rely on it for activation. Here’s how it works:
• CYP2D6 converts a portion of hydrocodone into hydromorphone, which is a more potent opioid and contributes to its pain-relieving effects.
• However, hydrocodone itself is already active and binds to opioid receptors, meaning CYP2D6 metabolism is not essential for its effectiveness (unlike codeine, which must be converted into morphine to work).
• CYP3A4 also plays a role, breaking hydrocodone into less active metabolites.
CYP2D6 Variability and Hydrocodone Response
• Poor metabolizers (PMs) of CYP2D6 (those with low or no enzyme activity) may experience weaker pain relief from hydrocodone because they produce less hydromorphone.
• Ultra-rapid metabolizers (UMs) may convert hydrocodone into hydromorphone too quickly, potentially leading to stronger effects or side effects.
So while CYP2D6 contributes to hydrocodone’s potency, it is not required for the drug to work, and its analgesic effect is still present in poor metabolizers, just potentially weaker.
But it seems to me that dilaudid should have worked on you
Dilaudid (hydromorphone) does not require CYP2D6 for activation because it is already in its active form. Unlike codeine, tramadol, or even hydrocodone (which partially depends on CYP2D6 for conversion into a more potent metabolite), hydromorphone works directly at opioid receptors without needing metabolic activation.
How Dilaudid Is Metabolized
• Hydromorphone is mainly metabolized in the liver by glucuronidation (via UGT2B7) into hydromorphone-3-glucuronide, which is inactive.
• CYP enzymes, including CYP2D6, play little to no role in its metabolism.
Implications
• CYP2D6 poor metabolizers (PMs) and ultra-rapid metabolizers (UMs) will generally not experience significant differences in response to hydromorphone.
• Patients who do not respond well to codeine or hydrocodone due to CYP2D6 issues may still get effective pain relief from hydromorphone.
So my best thinking is that you have a problem metabolizing opioids in your liver.
Something like this might be true for you.
If you don’t feel the effects of hydrocodone, several factors could be at play. Here are the most likely reasons:
1. CYP2D6 Poor Metabolism (Reduced Conversion to Hydromorphone)
• Hydrocodone is partially metabolized by CYP2D6 into hydromorphone, which is more potent.
• If you are a CYP2D6 poor metabolizer (PM) (due to genetic variations), your body may not efficiently convert hydrocodone into hydromorphone, leading to reduced pain relief.
• You can get a pharmacogenetic test to check your CYP2D6 status.
2. CYP3A4 Overactivity (Rapid Breakdown of Hydrocodone)
• Hydrocodone is also broken down by CYP3A4 into an inactive metabolite.
• If your CYP3A4 activity is high, hydrocodone might be metabolized too quickly before it has time to work.
• Certain medications (e.g., rifampin, St. John’s Wort) can increase CYP3A4 activity, making hydrocodone less effective.
3. High Opioid Tolerance or Natural Insensitivity
• If you’ve used opioids before, you may have a higher opioid tolerance, requiring a stronger dose.
• Some people have naturally lower opioid sensitivity due to genetic variations in the OPRM1 gene (mu-opioid receptor).
4. Pain Type (Neuropathic Pain or Hyperalgesia)
• Hydrocodone is most effective for nociceptive pain (injury, surgery, inflammation).
• Neuropathic pain (nerve damage, fibromyalgia) often does not respond well to hydrocodone or opioids in general.
• Opioid-induced hyperalgesia (OIH) can paradoxically make pain worse instead of better.
5. Absorption and Other Physiological Factors
• If you have gastrointestinal issues (e.g., gastroparesis), your body might not absorb hydrocodone efficiently.
• Food and pH levels in your stomach can also influence absorption.
What You Can Do
• Try a different opioid: Since hydromorphone (Dilaudid) doesn’t rely on CYP2D6, it may work better for you.
• Consider non-opioid pain management: Depending on the cause of your pain, other medications (e.g., NSAIDs, gabapentinoids, SNRIs) may be more effective.
• Get pharmacogenetic testing: This can determine whether CYP2D6 or other enzymes are affecting your drug metabolism.
i used chat gpt to kind of help me with some of the research arriving at the problem metabolizing opioids hypothesis.
i used chat gpt to kind of help me with some of the research arriving at the problem metabolizing opioids hypothesis.
thank you for all the info you are a real
